Azaspiro[4.5]decane derivatives and use thereof

ABSTRACT

The invention provides azaspiro[4.5]decane derivatives of Formula (A): and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, wherein A 1 , X, A 2 , Rr, R 2′ , W 1 , W 2 , R 3′ , R 4′ , a, and b are defined in the disclosure. The invention also provides compounds of Formulae I, and B-G, and pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof. Further, the invention provides use of the compounds of Formulae A-G and I, and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides, and diastereomers thereof, to treat pain. In certain embodiments, Compounds of the Disclosure are useful for treating a disorder responsive to blockade of one or more sodium channels.

BACKGROUND OF THE INVENTION

Voltage-gated sodium channels (VGSCs) are found in all excitable cells.In neuronal cells of the central nervous system (CNS) and peripheralnervous system (PNS) sodium channels are primarily responsible forgenerating the rapid upstroke of the action potential. In this mannersodium channels are essential to the initiation and propagation ofelectrical signals in the nervous system. Proper function of sodiumchannels is therefore necessary for normal function of the neuron.Consequently, aberrant sodium channel function is thought to underlie avariety of medical disorders (See Hubner et al., Hum. Mol. Genet.11:2435-2445 (2002) for a general review of inherited ion channeldisorders) including epilepsy (Yogeeswari et al, Curr. Drug Target5:589-602 (2004)), arrhythmia (Noble, Proc. Natl. Acad. Sci. USA99:5755-5756 (2002)), myotonia (Cannon, Kidney Int. 57:772-779 (2000)),and pain (Wood et al., J. Neurobiol., 61:55-71 (2004)).

VGSCs are composed of one α-subunit, which forms the core of the channeland is responsible for voltage-dependent gating and ion permeation, andseveral auxiliary β-subunits (see, e.g., Chahine et al., CNS &Neurological Disorders-Drug Targets 7:144-158 (2008) and Kyle and Ilyin,J. Med. Chem. 50:2583-2588 (2007)). α-Subunits are large proteinscomposed of four homologous domains. Each domain contains six α-helicaltransmembrane spanning segments. There are currently nine known membersof the family of voltage-gated sodium channel α-subunits. Names for thisfamily include SCNx, SCNAx, and Na_(v)x.x (see TABLE 1, below). The VGSCfamily has been phylogenetically divided into two subfamilies Na_(v)1.x(all but SCN6A) and Na_(v)2.x (SCN6A). The Na_(v)1.x subfamily can befunctionally subdivided into two groups, those which are sensitive toblocking by tetrodotoxin (TTX-sensitive or TTX-s) and those which areresistant to blocking by tetrodotoxin (TTX-resistant or TTX-r).

There are three members of the subgroup of TTX-resistant sodiumchannels. The SCN5A gene product (Na_(v)1.5, Hl) is almost exclusivelyexpressed in cardiac tissue and has been shown to underlie a variety ofcardiac arrhythmias and other conduction disorders (Liu et al., Am. J.Pharmacogenomics 3:173-179 (2003)). Consequently, blockers of Na_(v)1.5have found clinical utility in treatment of such disorders (Srivatsa etal., Curr. Cardiol. Rep. 4:401-410 (2002)). The remaining TTX-resistantsodium channels, Na_(v)1.8 (SCNl0A, PN3, SNS) and Na_(v)1.9 (SCN11A,NaN, SNS2) are expressed in the peripheral nervous system and showpreferential expression in primary nociceptive neurons. Human geneticvariants of these channels have not been associated with any inheritedclinical disorder. However, aberrant expression of Na_(v)1.8 has beenfound in the CNS of human multiple sclerosis (MS) patients and also in arodent model of MS (Black et al., Proc. Natl. Acad. Sci. USA97:11598-115602 (2000)). Evidence for involvement in nociception is bothassociative (preferential expression in nociceptive neurons) and direct(genetic knockout). Na_(v)1.8-null mice exhibited typical nociceptivebehavior in response to acute noxious stimulation but had significantdeficits in referred pain and hyperalgesia (Laird et al., J. Neurosci.22:8352-8356 (2002)).

TABLE 1 Voltage-gated sodium channel gene family Gene Tissue TTX IC₅₀Disease Type Symbol Distribution (nM) Association Indications Na_(v)1.1SCN1A CNS/PNS 10 Epilepsy Pain, seizures, neurodegeneration Na_(v)1.2SCN2A CNS 10 Epilepsy Epilepsy, neurodegeneration Na_(v)1.3 SCN3A CNS 15— Pain Na_(v)1.4 SCN4A Skeletal muscle 25 Myotonia Myotonia Na_(v)1.5SCN5A Heart muscle 2,000 Arrhythmia Arrhythmia Na_(v)1.6 SCN8A CNS/PNS 6— Pain, movement disorders Na_(v)1.7 SCN9A PNS 25 Erythermalgia PainNa_(v)1.8 SCN10A PNS 50,000 — Pain Na_(v)1.9 SCN11A PNS 1,000 — Pain

The Na_(v)1.7 (PN1, SCN9A) VGSC is sensitive to blocking by tetrodotoxinand is preferentially expressed in peripheral sympathetic and sensoryneurons. The SCN9A gene has been cloned from a number of species,including human, rat, and rabbit and shows ˜90% amino acid identitybetween the human and rat genes (Toledo-Aral et al., Proc. Natl. Acad.Sci. USA 94:1527-1532 (1997)).

An increasing body of evidence suggests that Na_(v)1.7 plays a key rolein various pain states, including acute, inflammatory and/or neuropathicpain. Deletion of the SCN9A gene in nociceptive neurons of mice led toan increase in mechanical and thermal pain thresholds and reduction orabolition of inflammatory pain responses (Nassar et al., Proc. Natl.Acad. Sci. USA 101:12706-12711 (2004)).

Sodium channel-blocking agents have been reported to be effective in thetreatment of various disease states, and have found particular use aslocal anesthetics, e.g., lidocaine and bupivacaine, and in the treatmentof cardiac arrhythmias, e.g., propafenone and amiodarone, and epilepsy,e.g., lamotrigine, phenytoin and carbamazepine (see Clare et al., DrugDiscovery Today 5:506-510 (2000); Lai et al., Annu. Rev. Pharmacol.Toxicol. 44:371-397 (2004); Anger et al., J. Med. Chem. 44:115-137(2001), and Catterall, Trends Pharmacol. Sci. 8:57-65 (1987)). Each ofthese agents is believed to act by interfering with the rapid influx ofsodium ions.

Other sodium channel blockers such as BW619C89 and lifarizine have beenshown to be neuroprotective in animal models of global and focalischemia (Graham et al., J. Pharmacol. Exp. Ther. 269:854-859 (1994);Brown et al., British J. Pharmacol. 115:1425-1432 (1995)).

It has also been reported that sodium channel-blocking agents can beuseful in the treatment of pain, including acute, chronic, inflammatory,neuropathic, and other types of pain such as rectal, ocular, andsubmandibular pain typically associated with paroxysmal extreme paindisorder; see, for example, Kyle and Ilyin., J. Med. Chem. 50:2583-2588(2007); Wood et al., J. Neurobiol. 61:55-71 (2004); Baker et al., TRENDSin Pharmacological Sciences 22:27-31 (2001); and Lai et al., CurrentOpinion in Neurobiology 13:291-297 (2003); the treatment of neurologicaldisorders such as epilepsy, seizures, epilepsy with febrile seizures,epilepsy with benign familial neonatal infantile seizures, inheritedpain disorders, e.g., primary erthermalgia and paroxysmal extreme paindisorder, familial hemiplegic migraine, and movement disorder; and thetreatment of other psychiatric disorders such as autism, cerebellaratrophy, ataxia, and mental retardation; see, for example, Chahine etal., CNS & Neurological Disorders-Drug Targets 7:144-158 (2008) andMeisler and Kearney, J. Clin. Invest. 115:2010-2017 (2005). In additionto the above-mentioned clinical uses, carbamazepine, lidocaine andphenytoin are used to treat neuropathic pain, such as from trigeminalneuralgia, diabetic neuropathy and other forms of nerve damage (Taylorand Meldrum, Trends Pharmacol. Sci. 16:309-316 (1995)). Furthermore,based on a number of similarities between chronic pain and tinnitus,(Moller, Am. J. Otol. 18:577-585 (1997); Tonndorf, Hear. Res. 28:271-275(1987)) it has been proposed that tinnitus should be viewed as a form ofchronic pain sensation (Simpson, et al., Tip. 20:12-18 (1999)). Indeed,lidocaine and carbamazepine have been shown to be efficacious intreating tinnitus (Majumdar, B. et al., Clin. Otolaryngol. 8:175-180(1983); Donaldson, Laryngol. Otol. 95:947-951 (1981)).

Many patients with either acute or chronic pain disorders respond poorlyto current pain therapies, and the development of resistance orinsensitivity to opiates is common. In addition, many of the currentlyavailable treatments have undesirable side effects.

In view of the limited efficacy and/or unacceptable side-effects of thecurrently available agents, there is a pressing need for more effectiveand safer analgesics that work by blocking sodium channels.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides novel compoundsrepresented by Formula I or A, provided below, and pharmaceuticallyacceptable salts, solvates, hydrates, N-oxides, and diastereomersthereof, collectively referred to herein as “Compounds of theDisclosure.”

In another aspect, the present disclosure provides a method for treatingpain (e.g., acute pain, chronic pain, which includes but is not limitedto, neuropathic pain, postoperative pain, and inflammatory pain, orsurgical pain), comprising administering an effective amount of aCompound of the Disclosure to a mammal in need of such treatment.Specifically, the present disclosure provides a method for preemptive orpalliative treatment of pain by administering an effective amount of aCompound of the Disclosure to a mammal in need of such treatment.

In another aspect, the present disclosure provides Compounds of theDisclosure for use in treating pain in a mammal, e.g., acute pain,chronic pain, which includes, but is not limited to, neuropathic pain,postoperative pain, inflammatory pain, or surgical pain.

In another aspect, the present disclosure provides a method for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, comprising administering aneffective amount of a Compound of the Disclosure to a mammal in need ofsuch treatment.

In another aspect, the present disclosure provides the use of Compoundsof the Disclosure as blockers of one or more sodium (Na⁺) channels.

In another aspect, the present disclosure provides compounds assynthetic intermediates that can be used to prepare blockers of one ormore sodium (Na⁺) channels.

In another aspect, the present disclosure provides a method for treatinga disorder responsive to blockade of one or more sodium channels in amammal, comprising administering to the mammal an effective amount of aCompound of the Disclosure.

In yet another aspect, the present disclosure provides a pharmaceuticalcomposition comprising a Compound of the Disclosure and one or morepharmaceutically acceptable carriers.

The present disclosure further provides a pharmaceutical composition fortreating a disorder responsive to blockade of one or more sodium ionchannels, wherein the pharmaceutical composition comprises an effectiveamount of a Compound of the Disclosure in a mixture with one or morepharmaceutically acceptable carriers.

Another aspect of the present disclosure provides a method of modulatingone or more sodium channels in a mammal, comprising administering to themammal an effective amount of at least one Compound of the Disclosure.

In another aspect, the present disclosure provides a radiolabeledCompound of the Disclosure and the use of such compounds as radioligandsin any appropriately selected competitive binding assays and screeningmethodologies. Thus, the present disclosure further provides a methodfor screening a candidate compound for its ability to bind to a sodiumchannel or sodium channel subunit using a radiolabeled Compound of theDisclosure. In certain embodiments, the compound is radiolabeled with³H, ¹¹C, or ¹⁴C. This competitive binding assay can be conducted usingany appropriately selected methodology. In one embodiment, the screeningmethod comprises: i) introducing a fixed concentration of theradiolabeled compound to an in vitro preparation comprising a soluble ormembrane-associated sodium channel, subunit or fragment under conditionsthat permit the radiolabeled compound to bind to the channel, subunit orfragment, respectively, to form a conjugate; ii) titrating the conjugatewith a candidate compound; and iii) determining the ability of thecandidate compound to displace the radiolabeled compound from saidchannel, subunit or fragment.

In another aspect, the present disclosure provides a Compound of theDisclosure for use in the manufacture of a medicament for treating painin a mammal. In one embodiment, the present disclosure provides the useof a Compound of the Disclosure in the manufacture of a medicament forpalliative or preemptive treatment of pain, such as acute pain, chronicpain, or surgical pain.

In another aspect, the present disclosure provides a Compound of theDisclosure for use in the manufacture of a medicament for treatingstroke, neuronal damage resulting from head trauma, epilepsy, seizures,general epilepsy with febrile seizures, severe myoclonic epilepsy ininfancy, neuronal loss following global and focal ischemia, migraine,familial primary erythromelalgia, paroxysmal extreme pain disorder,cerebellar atrophy, ataxia, dystonia, tremor, mental retardation,autism, a neurodegenerative disorder (e.g., Alzheimer's disease,amyotrophic lateral sclerosis (ALS), or Parkinson's disease), manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia, in a mammal.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the invention is based on discovery of compoundsdelineated herein (referred to as “Compounds of the Disclosure”) thatare useful for treating pain in a subject (e.g., a mammal).

In certain embodiments, the Compounds of the Disclosure are useful asblockers of one or more sodium (Na⁺) channels. It is thus believed thatthe Compounds of the Disclosure are useful for treating disordersresponsive to the blockade of one or more sodium ion channels. Anotheraspect of the invention is based on the use of Compounds of theDisclosure as synthetic intermediates useful for preparing sodiumchannel blockers.

In one embodiment, Compounds of the Disclosure are compounds representedby Formula I:

and pharmaceutically acceptable salts and solvates thereof,

wherein:

R¹ is selected from the group consisting of:

R^(2a) and R^(2b) are each independently selected from the groupconsisting of: (a) hydrogen; (b) halo; (c) nitro; (d) cyano; (e)hydroxy; (f) amino; (g) alkylamino; (h) dialkylamino; (i) alkyl; (j)haloalkyl; (k) hydroxyalkyl; (l) alkoxy; (m) haloalkoxy; and (n)alkoxyalkyl;

R^(2c) and R^(2d) are each independently selected from the groupconsisting of: (a) hydrogen; (b) halo; (c) nitro; (d) cyano; (e)hydroxy; (f) amino; (g) alkylamino; (h) dialkylamino; (i) alkyl; (j)haloalkyl; (k) hydroxyalkyl; (l) alkoxy; (m) haloalkoxy; and (n)alkoxyalkyl;

is a single bond or a double bond;

X¹ is selected from the group consisting of O and NR³;

X² is selected from the group consisting of CH₂ and C═O;

R³ is selected from the group consisting of hydrogen and alkyl;

R^(4a) is selected from the group consisting of hydrogen and alkyl;

R^(4b) and R^(4c) are each independently selected from the groupconsisting of hydrogen, alkyl, and optionally substituted aryl;

R^(5a) is selected from the group consisting of: (a) hydrogen; (b) halo;(c) nitro; (d) cyano; (e) hydroxy; (f) amino; (g) alkylamino; (h)dialkylamino; (i) haloalkyl; (j) hydroxyalkyl; (k) alkoxy; (l)haloalkoxy; (m) alkoxyalkyl; and (n) —Z—R⁹;

R^(5b) is selected from the group consisting of: (a) hydrogen; (b) halo;(c) nitro; (d) cyano; (e) hydroxy; (f) amino; (g) alkylamino; (h)dialkylamino; (i) haloalkyl; (j) hydroxyalkyl; (k) alkoxy; (l)haloalkoxy; and (m) alkoxyalkyl;

E is selected from the group consisting of: (a) hydroxy; (b) alkoxy; and(c) —NR⁶R⁷;

R⁶ is selected from the group consisting of: (a) hydrogen; (b) alkyl;(c) aralkyl; (d) (heterocyclo)alkyl; (e) (heteroaryl)alkyl; (f)(amino)alkyl; (g) (alkylamino)alkyl; (h) (dialkylamino)alkyl; (i)(carboxamido)alkyl; (j) (cyano)alkyl; (k) alkoxyalkyl; (l) hydroxyalkyl;and (m) heteroalkyl;

R⁷ is selected from the group consisting of hydrogen and alkyl; or

R⁶ and R⁷ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

Z is selected from the group consisting of —NR⁸— and —O—;

R⁸ is selected from the group consisting of: (a) hydrogen; (b) alkyl;and (c) hydroxyalkyl;

R⁹ is selected from the group consisting of:

and

(c) hydroxyalkyl; or

R⁸ and R⁹ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

R¹⁰ is selected from the group consisting of: (a) hydrogen; (b)optionally substituted alkyl; (c) aralkyl; (d) (heterocyclo)alkyl; (e)(heteroaryl)alkyl; (f) (amino)alkyl; (g) (alkylamino)alkyl; (h)(dialkylamino)alkyl; (i) (carboxamido)alkyl; (j) (cyano)alkyl; (k)alkoxyalkyl; (l) hydroxyalkyl; (m) heteroalkyl; (n) optionallysubstituted cycloalkyl; (o) optionally substituted aryl; (p) optionallysubstituted heterocyclo; and (q) optionally substituted heteroaryl;

R¹¹ is selected from the group consisting of: (a) hydroxy; (b) alkoxy;and (c) —NR^(13a)R^(13b);

R^(13a) is selected from the group consisting of: (a) hydrogen; (b)alkyl; (c) aralkyl; (d) (heterocyclo)alkyl; (e) (heteroaryl)alkyl; (f)(amino)alkyl; (g) (alkylamino)alkyl; (h) (dialkylamino)alkyl; (i)(carboxamido)alkyl; (j) (cyano)alkyl; (k) alkoxyalkyl; (l) hydroxyalkyl;and (m) heteroalkyl;

R^(13b) is selected from the group consisting of hydrogen and alkyl; or

R^(13a) and R^(13b) taken together with the nitrogen atom to which theyare attached form a 3- to 8-membered optionally substituted heterocyclo;

R¹² is selected from the group consisting of hydrogen and alkyl; and

s is 1, 2, or 3.

Further, the invention also includes hydrates, N-oxides, anddiastereomers thereof of compounds represented by Formula I.

In a separate aspect, the invention provides a compound of Formula A, ora pharmaceutically acceptable salt, solvate, hydrate, N-oxide, ordiastereomer thereof:

Wherein

a and b, each independently, are 0, 1, or 2, provided that at least oneof a and b is a value other than 0;

n is 0, 1, or 2;

o is 0 or 1;

m, each independently, is 0, 1, or 2;

W¹ is —(CR^(5′)R^(6′))_(n)—U—;

W² is —(CR^(7′)R^(8′))_(o)-G-;

U is absent, N(R^(1a′)) or O, provided that when n is 0, then U isN(R^(1a′)) or O;

G is absent, N(R^(1b′)) or O, provided that when o is 0, then G isN(R^(1b′)) or O;

R^(1′) and R^(2′), each independently, are H, optionally-substitutedalkyl, alkoxy, cyano, alkenyl, carboxamido, and nitro; or R and R^(2′),taken with the carbon atom they are attached to, form a carbonyl group;

R^(3′) and R^(4′), each independently, are H, optionally-substitutedalkyl, alkoxy, cyano, alkenyl, carboxamido, and nitro; or R^(3′) andR^(4′), taken with the carbon atom they are attached to, form a carbonylgroup;

R^(5′) and R^(6′), each independently, are H, alkyl, haloalkyl,—S(O)_(m)—R^(9′), alkoxy, haloalkoxy, amino, (alkyl)amino,(dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl, (dihydroxy)alkyl,nitro, or sulfonamido;

-   -   or R^(5′) and R^(6′), taken together with the carbon atom to        which they are both directly attached, form carbonyl, 3- to        8-membered optionally-substituted heterocyclo, or 3- to        8-membered optionally-substituted cycloalkyl;    -   or R^(1′) and R^(5′), together with carbon atoms to which they        are respectively attached, are fused to form a carbon-carbon        double bond;    -   or R^(1′), R^(2′), one R^(5′), and one R^(6′), together with        carbon atoms to which they are respectively attached, are fused        to form optionally-substituted aryl or optionally-substituted 5-        to 6-membered heteroaryl;    -   or one R^(5′), one R^(6′), R^(3′) and R^(4′), together with        carbon atoms to which they are respectively attached, are fused        to form optionally-substituted aryl or optionally-substituted 5-        to 6-membered heteroaryl, wherein said one R^(5′) and said one        R^(6′) are attached to a same carbon atom;

R^(1a′) is H, optionally-substituted alkyl, optionally-substituted aryl,optionally-substituted cycloalkyl, optionally-substituted(alkoxy)carbonyl, carboxamido, optionally-substituted((amino)alkyl)carbonyl, or optionally-substituted (alkyl)carbonyl; orR^(1a′) and R^(1′), taken together with the bonds they are attached to,form a 5- to 8-membered optionally-substituted heterocyclo;

R^(7′) and R^(8′), each independently, are H, alkyl, haloalkyl,—S(O)_(m)—R^(9′), alkoxy, haloalkoxy, amino, (alkyl)amino,(dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl, (dihydroxy)alkyl,nitro, or sulfonamido;

-   -   or R^(7′) and R^(8′), taken together with the carbon atom to        which they are attached, form 3- to 8-membered optionally        substituted heterocyclo, or a 3- to 8-membered        optionally-substituted cycloalkyl;    -   or R^(3′) and R^(7′), together with carbon atoms to which they        are respectively attached, are fused to form a carbon-carbon        double bond;    -   or R^(3′), R^(4′), one R^(7′), and one R^(8′), together with        carbon atoms to which they are respectively attached, are fused        to form optionally-substituted aryl or optionally-substituted 5-        to 6-membered heteroaryl, wherein said one R^(7′) and said one        R^(8′) are attached to a same carbon atom;

R^(1b′) is H, optionally-substituted alkyl, optionally-substituted aryl,optionally-substituted cycloalkyl, optionally-substituted(alkoxy)carbonyl, carboxamido, optionally-substituted((amino)alkyl)carbonyl, or optionally-substituted (alkyl)carbonyl; orR^(1b′) and R³, taken together with the bonds they are attached to, forma 5- to 8-membered optionally-substituted heterocyclo;

A¹ is selected from the group consisting of:

-   -   a) optionally-substituted 3- to 8-membered heterocyclo;    -   b) optionally-substituted aryl; and    -   c) optionally-substituted 6-membered heteroaryl;

A² is selected from the group consisting of:

-   -   i) absent;    -   ii) optionally-substituted 3- to 8-membered heterocyclo;    -   iii) optionally-substituted aryl; and    -   iv) optionally-substituted 6-membered heteroaryl;

X is absent, —O—, —N(R^(10′))—, —SO₂N(R^(11′))—, or —C(O)O—, providedthat when A² is absent, then X is absent or —C(O)O—;

R^(9′) is optionally-substituted alkyl, optionally-substitutedcycloalkyl, optionally-substituted heteroaryl, or optionally-substitutedheterocyclo;

R^(10′) and R^(11′), each independently, are H or optionally-substitutedalkyl.

In one embodiment of Formula A, a is 1. In another embodiment of FormulaA, b is 1. A separate embodiment provides that both of a and b are 1 inFormula A.

One embodiment of Formula A provides that A² is optionally-substitutedaryl (e.g., phenyl, naphthyl, etc).

In another embodiment of Formula A, A² is optionally-substituted6-membered heteroaryl (e.g., pyridyl, diazinyl, triazinyl, etc).Non-limiting diazinyl groups include pyrimidyl (i.e., 1,3-diazinyl),pyrazinyl (i.e., 1,4-diazinyl), and pyridazyl (i.e., 1,2-diazinyl).Non-limiting triazinyl groups include 1,2,3-triazinyl, 1,2,4-triazinyl,and 1,3, 5-triazinyl.

In certain embodiments of compounds of Formula A and pharmaceuticallyacceptable salts, solvates, hydrates, N-oxides, and diastereomersthereof, A² is selected from the group consisting of phenyl, pyridyl,pyrimidyl, and triazinyl, each of which is optionally substituted, e.g.,by one, two, three, or four substituents independently selected from thegroup of optional substituents suitable for aryl and/or heteroarylgroups as discussed infra.

In one embodiment of Formula A, R^(1a′) is R^(4b) as defined in FormulaI; that is, R^(1a′) is hydrogen, alkyl, or optionally-substituted aryl.A separate embodiment of Formula A provides that R^(1b′) is R^(4c) asdefined in Formula I; that is, R^(1b′) is hydrogen, alkyl, oroptionally-substituted aryl.

In another embodiment of Formula A, R^(1a′) is R^(4a) as defined inFormula I; that is, R^(1a′) is hydrogen or alkyl. A separate embodimentof Formula A provides that R^(1b′) is phenyl substituted by R^(2c) andR^(2d), wherein R^(2c) and R^(2d) are defined in Formula I.

In another embodiment, the invention provides a compound of Formula B,or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, ordiastereomer thereof:

Wherein

Q¹, Q², and Q³, each independently, are CH or N;

X is absent, —O—, or —N(R^(10′))—;

A¹ is optionally-substituted aryl or optionally-substituted 6-memberedheteroaryl;

W¹ is —(CR^(5′)R^(6′))_(n)—U—;

W² is —(CR^(7′)R^(8′))_(o)-G-;

n is 0 or 1;

o is 0 or 1;

U is absent, N(R^(1a′)) or O, provided that when n is 0, then U isN(R^(1a′)) or O;

G is absent, N(R^(1b′)) or O, provided that when o is 0, then G isN(R^(1b′)) or O;

R^(1′) and R^(2′), each independently, are H, optionally-substitutedalkyl, alkoxy, cyano, alkenyl, carboxamido, or nitro; or R^(1′) andR^(2′), taken with the carbon atom they are attached to, form a carbonylgroup;

R^(3′) and R^(4′), each independently, are H, optionally-substitutedalkyl, alkoxy, cyano, alkenyl, carboxamido, or nitro; or R^(3′) andR^(4′), taken with the carbon atom they are attached to, form a carbonylgroup;

R^(5′) and R^(6′), each independently, are H, alkyl, haloalkyl, alkoxy,haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano,(hydroxy)alkyl, (dihydroxy)alkyl, or sulfonamido; or R^(5′) and R^(6′),taken together with the carbon atom to which they are attached, form a3- to 8-membered optionally substituted heterocyclo or a 3- to8-membered optionally-substituted cycloalkyl;

R^(1a′) is H, optionally-substituted alkyl, optionally-substituted aryl,optionally-substituted (alkoxy)carbonyl, or carboxamido; or R^(1a′) andR^(1′), taken together with the bonds they are attached to, form a 5- to8-membered optionally-substituted heterocyclo;

R^(7′) and R^(8′), each independently, are H, alkyl, haloalkyl, alkoxy,haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano,(hydroxy)alkyl, (dihydroxy)alkyl, or sulfonamido; or R^(7′) and R^(8′),taken together with the carbon atom to which they are attached, form a3- to 8-membered optionally substituted heterocyclo or a 3- to8-membered optionally-substituted cycloalkyl;

R^(1b′) is H, optionally-substituted alkyl, optionally-substituted aryl,optionally-substituted (alkoxy)carbonyl, or carboxamido; or R^(1b′) andR^(3′), taken together with the bonds they are attached to, form a 5- to8-membered optionally-substituted heterocyclo;

R^(10′) is H or optionally-substituted alkyl;

j is 0, 1, 2, or 3;

R^(d) each independently is selected from the group consisting of:

-   -   a) hydrogen;    -   b) halo;    -   c) nitro;    -   d) cyano;    -   e) hydroxy;    -   f) amino;    -   g) alkylamino;    -   h) dialkylamino;    -   i) optionally-substituted (heterocyclo)amino;    -   j) haloalkyl;    -   k) hydroxyalkyl;    -   l) alkoxy;    -   m) haloalkoxy;    -   n) alkoxyalkyl;    -   o) carboxamido;    -   p) optionally-substituted (heterocyclo)alkyl;    -   q) optionally-substituted (cycloalkyl)alkyl;    -   r) (alkoxy)carbonyl;    -   s) —COOH;    -   t) (carboxamido)(hydroxy)alkyl; and    -   u) optionally-substituted ((heterocyclo)amino)alkyl.

One embodiment in accordance with Formula A or B provides that W¹ is—(CR^(5′)R^(6′))_(n)—U—, and n is 0. Accordingly, W¹ is —U—, and U isN(R^(1a′)) or O. In one embodiment, W¹ is —U—, U is N(R^(1a′)), andR^(1a′) is H. In another embodiment, W¹ is —U—, U is N(R^(1a′)), andR^(1a′) is optionally-substituted aryl (e.g., phenyl). In anotherembodiment, W¹ is —U—, and U is O.

Another embodiment of Formula A or B provides that W² is—(CR^(7′)R^(8′))_(o)-G-, and o is 0. Accordingly, W² is -G-, and G isN(R^(1b′)) or O. In one embodiment, W² is -G-, G is N(R^(1b′)), andR^(1b′) is H. In another embodiment, W² is -G-, G is N(R^(1b′)), andR^(1b′) is optionally-substituted aryl (e.g., phenyl). In anotherembodiment, W² is -G-, and G is O.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula A or B, and the pharmaceutically acceptablesalts, solvates, hydrates, N-oxides, or diastereomers thereof, whereinR^(1′) and R^(2′), taken with the carbon atom they are attached to, forma carbonyl group.

In one embodiment, Compounds of the Disclosure are compounds representedby Formula A or B, and the pharmaceutically acceptable salts, solvates,hydrates, N-oxides, or diastereomers thereof, wherein R^(3′) and R^(4′)are both H. In another embodiment, Compounds of the Disclosure arecompounds represented by Formula A or B, and the pharmaceuticallyacceptable salts, solvates, hydrates, N-oxides, or diastereomersthereof, wherein R^(3′) and R^(4′), taken with the carbon atom they areboth attached to, form a carbonyl group.

One embodiment of Formula B provides that at least one of Q¹, Q² and Q³is CH. For example, all of Q¹, Q² and Q³ are CH. Alternatively, two ofQ¹, Q² and Q³ are CH, and the other is N. Further alternatively, one ofQ¹, Q² and Q³ is CH, and the other two are N.

One embodiment of Formula A or B provides that A¹ is phenyl, which isfurther optionally substituted by one, two, three, or four substituentsindependently selected from those discussed below (including theoptional substituents suitable for an aryl group as defined infra.). Inanother embodiment of Formula A or B, A¹ is 6-membered heteroaryl, whichis further optionally substituted by one, two, three, or foursubstituents independently selected from those discussed below(including the optional substituents for a heteroaryl group as definedinfra.).

In yet another embodiment, the present disclosure provides a compound ofFormula C, or a pharmaceutically acceptable salt, solvate, hydrate,N-oxide, or diastereomer thereof:

Wherein

Q³ is CH or N;

X is absent or —O—;

U is N(R^(1a′)) or O;

G is N(R^(1b′)) or O;

R^(1a′) is H, alkyl, or aryl, wherein each of said alkyl and said arylis optionally substituted by one to three substituents independentlyselected from the group of halogen, hydroxy, carboxamido, amino,alkylamino, (heterocyclo)amino, alkoxy, haloalkoxy, and haloalkyl;

R^(1b′) is H, alkyl, or aryl, wherein each of said alkyl and said arylis optionally substituted by one to three substituents independentlyselected from the group of halogen, hydroxy, carboxamido, amino,alkylamino, (heterocyclo)amino, alkoxy, haloalkoxy, and haloalkyl;

R^(d) is selected from the group consisting of:

-   -   a) hydrogen;    -   b) halo;    -   c) amino;    -   d) alkylamino;    -   e) dialkylamino;    -   f) optionally-substituted (heterocyclo)amino;    -   g) haloalkyl;    -   h) hydroxyalkyl;    -   i) alkoxy;    -   j) haloalkoxy;    -   k) alkoxyalkyl;    -   l) carboxamido;    -   m) optionally-substituted (heterocyclo)alkyl;    -   n) (carboxamido)(hydroxy)alkyl; and    -   o) optionally-substituted ((heterocyclo)amino)alkyl;

R^(e) and R^(f) independently are selected from the group consisting of:

-   -   a) hydrogen;    -   b) halo;    -   c) hydroxy;    -   d) amino;    -   e) alkylamino;    -   f) dialkylamino;    -   g) optionally-substituted (heterocyclo)amino;    -   h) haloalkyl;    -   j) hydroxyalkyl;    -   k) alkoxy;    -   l) haloalkoxy;    -   m) carboxamido; and    -   o) optionally-substituted (heterocyclo)alkyl.

In one embodiment of Formula C, R^(d) is H. Another embodiment providesthat R^(d) is carboxamido. Another embodiment of Formula C provides thatR^(d) is hydroxyalkyl. Under certain circumstances, hydroxyalkylincludes, e.g., (monohydroxy)alkyl or (hydroxy)alkyl, (dihydroxy)alkyl,and (multihydroxy)alkyl.

A separate embodiment of Formula C provides that R^(e) is H, and R^(f)is selected from the group consisting of a) halo; b) amino; c)alkylamino; d) dialkylamino; e) (heterocyclo)amino optionallysubstituted by one to two substituents independently selected from thegroup of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, and carboxamido; f)haloalkyl; g) hydroxyalkyl; h) alkoxy; i) haloalkoxy; j) carboxamido;and k) (heterocyclo)alkyl optionally substituted by one to twosubstituents independently selected from the group of halo, alkyl,haloalkyl, alkoxy, haloalkoxy, and carboxamido.

In one embodiment of the compounds of Formula C or pharmaceuticallyacceptable salts, solvates, hydrates, N-oxides, or diastereomersthereof, X is absent. Another embodiment provides that X is —O—.

Further, the present disclosure provides a compound of Formula D, or apharmaceutically acceptable salt, solvate, hydrate, N-oxide, ordiastereomer thereof:

wherein U, G, Q³, and R^(f) are defined above (e.g., those defined inany one of Formulae A to C respectively).

In still another embodiment, the present disclosure provides a compoundof Formula E, or a pharmaceutically acceptable salt, solvate, hydrate,N-oxide, or diastereomer thereof:

Wherein U, G, Q³, and R^(f) are defined above (e.g., those defined inany one of Formulae A to C respectively).

In one embodiment of Formula A, B, C, D, or E, U is N(R^(1a′)). Inanother embodiment of Formula A, B, C, D, or E, G is N(R^(1b′)). Aseparate embodiment provides compounds of Formula A, B, C, D, or E, orpharmaceutically acceptable salts, solvates, hydrates, N-oxides, ordiastereomers thereof, U is N(R^(1a′)) and G is N(R^(1b′)). Oneembodiment provides that U is N(R^(1a′)) and G is N(R^(1b′)), whereinR^(1a′) is H, and R^(1b′) is H.

Still further, one embodiment in accordance with Formula A provides thatA² is absent. In one embodiment of Formula A, X is absent. Oneembodiment of Formula A provides that both of A² and X are absent.Another embodiment provides that A¹ is 6-membered heteroaryl, which isoptionally substituted. For example, A¹ is 6-membered heteroaryloptionally substituted by one to three substituents independentlyselected from the group of optional substituents independently selectedfrom those discussed below, including, such as, the optionalsubstituents suitable for heteroaryl (as defined infra.). Also, incertain embodiments, the optional substituents to the 6-memberedheteroaryl are selected from the group consisting of R^(5a), R^(5b), and—C(O)E as those defined in Formula I. For example, the optionalsubstituents to the 6-membered heteroaryl can be selected from the groupconsisting of: a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f)amino; g) alkylamino; h) dialkylamino; i) haloalkyl; j) hydroxyalkyl; k)alkoxy; l) haloalkoxy; m) alkoxyalkyl; n) —C(O)E (wherein E is hydroxy,alkoxy, or —NR⁶R⁷); and p) —Z—R⁹; wherein R⁶, R⁷, Z, and R⁹ are those asdefined in Formula I.

One embodiment of Formula A provides that both of A² and X are absent,A¹ is pyrimidyl substituted by R^(5a), R^(5b), and —C(O)E, whereinR^(5a), R^(5b), and E are defined in Formula I.

In a further embodiment of Formulae I or A, a compound of the presentdisclosure is a compound of Formula F or a pharmaceutically acceptablesalt, solvate, hydrate, N-oxide, or diastereomer thereof:

Wherein R^(4b), R^(4c), E, R^(5a), and R^(5b) are those as defined inFormula I.

Certain embodiments of Formula F provide that

R^(4b) and R^(4c), each independently, are selected from the groupconsisting of hydrogen, alkyl, and optionally substituted aryl (e.g.,phenyl);

R^(5a) is selected from the group consisting of a) hydrogen; b) halo; c)nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino;i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy; m) alkoxyalkyl;and n) —Z—R⁹;

R^(5b) is selected from the group consisting of: a) hydrogen; b) halo;c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h)dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy;and m) alkoxyalkyl;

E is selected from the group consisting of: a) hydroxy; b) alkoxy; andc) —NR⁶R⁷;

R⁶ is selected from the group consisting of: a) hydrogen; b) alkyl; c)aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl;g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j)(cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl;

R⁷ is hydrogen or alkyl; or

R⁶ and R⁷ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

Z is selected from the group consisting of —NR⁸— and —O—;

R⁸ is selected from the group consisting of: a) hydrogen; b) alkyl; andc) hydroxyalkyl;

R⁹ is selected from the group consisting of:

and

-   -   c) hydroxyalkyl; or

R⁸ and R⁹ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

R¹⁰ is selected from the group consisting of: a) hydrogen; b) optionallysubstituted alkyl; c) aralkyl; d) (heterocyclo)alkyl; e)(heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h)(dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k)alkoxyalkyl; l) hydroxyalkyl; m) heteroalkyl; n) optionally substitutedcycloalkyl; o) optionally substituted aryl; p) optionally substitutedheterocyclo; and q) optionally substituted heteroaryl;

R¹¹ is selected from the group consisting of: a) hydroxy; b) alkoxy; andc) —NR^(13a)R^(13b);

R^(13a) is selected from the group consisting of: a) hydrogen; b) alkyl;c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f)(amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i)(carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl;and m) heteroalkyl;

R^(13b) is hydrogen or alkyl; or

R^(13a) and R^(13b) taken together with the nitrogen atom to which theyare attached form a 3- to 8-membered optionally substituted heterocyclo;

R¹² is selected from the group consisting of hydrogen and alkyl; and

s is 1, 2, or 3.

In another embodiment of Formulae I or A, a compound of the presentdisclosure is a compound of Formula G, or a pharmaceutically acceptablesalt, solvate, hydrate, N-oxide, or diastereomer thereof:

Wherein R^(2c), R^(2d), R^(4a), E, R^(5a), and R^(5b) are those as abovedefined in Formula I.

For example, the invention provides a compound of Formula G, or apharmaceutically acceptable salt, solvate, hydrate, N-oxide, ordiastereomer thereof, wherein

R^(2c) and R^(2d) are each independently selected from the groupconsisting of: a) hydrogen; b) halo; c) nitro; d) cyano; e) hydroxy; f)amino; g) alkylamino; h) dialkylamino; i) alkyl; j) haloalkyl; k)hydroxyalkyl; l) alkoxy; m) haloalkoxy; and n) alkoxyalkyl;

R^(4a) is hydrogen or alkyl;

R^(5a) is selected from the group consisting of a) hydrogen; b) halo; c)nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h) dialkylamino;i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy; m) alkoxyalkyl;and n) —Z—R⁹;

R^(5b) is selected from the group consisting of: a) hydrogen; b) halo;c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h)dialkylamino; i) haloalkyl; j) hydroxyalkyl; k) alkoxy; l) haloalkoxy;and m) alkoxyalkyl;

E is selected from the group consisting of: a) hydroxy; b) alkoxy; andc) —NR⁶R⁷;

R⁶ is selected from the group consisting of: a) hydrogen; b) alkyl; c)aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f) (amino)alkyl;g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i) (carboxamido)alkyl; j)(cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl; and m) heteroalkyl;

R⁷ is hydrogen or alkyl; or

R⁶ and R⁷ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

Z is selected from the group consisting of —NR⁸— and —O—;

R⁸ is selected from the group consisting of: a) hydrogen; b) alkyl; andc) hydroxyalkyl;

R⁹ is selected from the group consisting of:

and

-   -   c) hydroxyalkyl; or

R⁸ and R⁹ taken together with the nitrogen atom to which they areattached form a 3- to 8-membered optionally substituted heterocyclo;

R¹⁰ is selected from the group consisting of: a) hydrogen; b) optionallysubstituted alkyl; c) aralkyl; d) (heterocyclo)alkyl; e)(heteroaryl)alkyl; f) (amino)alkyl; g) (alkylamino)alkyl; h)(dialkylamino)alkyl; i) (carboxamido)alkyl; j) (cyano)alkyl; k)alkoxyalkyl; l) hydroxyalkyl; m) heteroalkyl; n) optionally substitutedcycloalkyl; o) optionally substituted aryl; p) optionally substitutedheterocyclo; and q) optionally substituted heteroaryl;

R¹¹ is selected from the group consisting of: a) hydroxy; b) alkoxy; andc) —NR^(13a)R^(13b);

R^(13a) is selected from the group consisting of: a) hydrogen; b) alkyl;c) aralkyl; d) (heterocyclo)alkyl; e) (heteroaryl)alkyl; f)(amino)alkyl; g) (alkylamino)alkyl; h) (dialkylamino)alkyl; i)(carboxamido)alkyl; j) (cyano)alkyl; k) alkoxyalkyl; l) hydroxyalkyl;and m) heteroalkyl;

R^(13b) is hydrogen or alkyl; or

R^(13a) and R^(13b) taken together with the nitrogen atom to which theyare attached form a 3- to 8-membered optionally substituted heterocyclo;

R¹² is selected from the group consisting of hydrogen and alkyl; and

s is 1, 2, or 3.

In one embodiment, Compounds of the Disclosure are compounds representedby Formula I, F, or G, and the pharmaceutically acceptable salts andsolvates thereof, wherein R^(5b) is hydrogen.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, F, or G, and the pharmaceutically acceptablesalts and solvates thereof, wherein R^(5a) is —Z—R⁹, and R^(5b) ishydrogen. One embodiment provides that Z is —NR⁸—, and R⁹ is

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I, F, and G, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(5a) is hydroxyalkyl,R^(5b) is hydrogen.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I, F, and G, and the pharmaceuticallyacceptable salts and solvates thereof, wherein E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I, F, and G, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(5a) is —Z—R⁹, Z is—NH— or —O—, R⁹ is

and R¹¹ is —NH₂. In one embodiment, R^(5b) is hydrogen. In anotherembodiment, R^(5b) is hydrogen and E is NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I, F, and G, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(5a) is —Z—R⁹, Z is—NH— or —O— and R⁹ is

In one embodiment, R^(5b) is hydrogen. In another embodiment, R^(5b) ishydrogen and E is NH₂.

In still another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I, F, and G, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(5a) is —Z—R⁹, R⁹ isselected from the group consisting of:

and R¹⁰ is C₁-C₄ alkyl. In one embodiment, R^(5b) is hydrogen. Inanother embodiment, R^(5b) is hydrogen and E is NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I, F, and G, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(5a) is —Z—R⁹, R⁹ isselected from the group consisting of:

R¹⁰ is C₁-C₄ alkyl, and Z is —NH—. In another embodiment, R^(5b) ishydrogen. In another embodiment, R^(5b) is hydrogen and E is NH₂.

In one embodiment, Compounds of the Disclosure are compounds representedby any one of Formulae I, F, and G, and the pharmaceutically acceptablesalts and solvates thereof, wherein R^(5a) is —Z—R⁹, and R⁹ is selectedfrom the group consisting of:

In another embodiment, R^(5b) is hydrogen. In another embodiment, R^(5b)is hydrogen and E is NH₂.

In yet another embodiment, Compounds of the Disclosure are compoundsrepresented by any one of Formulae I, F, and G, and the pharmaceuticallyacceptable salts and solvates thereof, wherein R^(5a) is —Z—R⁹, R⁹ isselected from the group consisting of:

and Z is —NH—. In one embodiment, R^(5b) is hydrogen. In anotherembodiment, R^(5b) is hydrogen and E is NH₂.

Further, Compounds of the Disclosure includes compounds represented byFormula I, and the pharmaceutically acceptable salts and solvatesthereof, wherein R¹ is R¹-I, and R^(2a), R^(2b), R^(5a), R^(5b), and Eare as defined in connection with Formula I. In one embodiment, R^(2a)and R^(2b) are hydrogen. In another embodiment,

is a double bond. In another embodiment, R^(5a) is —Z—R⁹. In anotherembodiment, R^(5a) is —Z—R⁹ and R^(5b) is hydrogen. In anotherembodiment, R^(5a) is —Z—R⁹. R^(5b) is hydrogen, and E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is R¹-II, and R^(2a), R^(2b), X¹, R^(5a),R^(5b), and E are as defined in connection with Formula I. In oneembodiment, R^(2a) and R^(2b) are hydrogen. In another embodiment, X¹ isoxygen. In another embodiment, R^(5a) is —Z—R⁹. In another embodiment,R^(5a) is —Z—R⁹ and R^(5b) is hydrogen. In another embodiment, R^(5a) is—Z—R⁹, R^(5b) is hydrogen, and E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is R¹-III, and R^(2a), R^(2b), X¹, R^(5a),R^(5b), and E are as defined in connection with Formula I. In oneembodiment, R^(2a) and R^(2b) are hydrogen. In another embodiment, X¹ isoxygen. In another embodiment, R^(5a) is —Z—R⁹. In another embodiment,R^(5a) is —Z—R⁹ and R^(5b) is hydrogen. In another embodiment, R^(5a) is—Z—R⁹, R^(5b) is hydrogen, and E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is R¹-IV, and R^(2a), R^(2b), X¹, R^(5a),R^(5b), and E are as defined in connection with Formula I. In oneembodiment, R^(2a) and R^(2b) are hydrogen. In another embodiment, X¹ isoxygen. In another embodiment, R^(5a) is —Z—R⁹. In another embodiment,R^(5a) is —Z—R⁹ and R^(5b) is hydrogen. In another embodiment, R^(5a) is—Z—R⁹, R^(5b) is hydrogen, and E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is R¹-V, and R^(2c), R^(2d), R^(4a),R^(5a), R^(5b), and E are as defined in connection with Formula I. Inone embodiment, R^(2c) and R^(2d) are hydrogen. In another embodiment,R^(4a) is hydrogen. In another embodiment, R^(5a) is —Z—R⁹. In anotherembodiment, R^(5a) is —Z—R⁹ and R^(5b) is hydrogen. In anotherembodiment, R^(5a) is —Z—R⁹, R^(5b) is hydrogen, and E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is R¹-VI, and R^(2a), R^(2b), X², R^(5a),R^(5b), and E are as defined in connection with Formula I. In oneembodiment, R^(2a) and R^(2b) are hydrogen. In another embodiment, X² isC═O. In another embodiment, X² is CH₂. In another embodiment, R^(5a) is—Z—R⁹. In another embodiment, R^(5a) is —Z—R⁹ and R^(5b) is hydrogen. Inanother embodiment, R^(5a) is —Z—R⁹, R^(5b) is hydrogen, and E is —NH₂.

In another embodiment, Compounds of the Disclosure are compoundsrepresented by Formula I, and the pharmaceutically acceptable salts andsolvates thereof, wherein R¹ is R¹-VII, and R^(4b), R^(4c), R^(5a),R^(5b), and E are as defined in connection with Formula I. In oneembodiment, R^(5a) is —Z—R⁹. In another embodiment, R^(5a) is —Z—R⁹ andR^(5b) is hydrogen. In another embodiment, R^(5a) is —Z—R⁹, R^(5b) ishydrogen, and E is —NH₂.

In one embodiment, Compounds of the Disclosure are compounds of TABLE 2,and the pharmaceutically acceptable salts, solvates, hydrates, N-oxides,and diastereomers thereof.

TABLE 2 Cpd. No. Structure Name 8

(S)-6-((2-oxopyrrolidin-3-yl)amino)- 2-(3H-spiro[isobenzofuran-1,4′-piperidin]-1′-yl)pyrimidine-4- carboxamide 9

(S)-6-((2-oxopyrrolidin-3-yl)amino)- yl)amino)-2-(spiro[indene-1,4′-piperidin]-1′-yl)pyrimidine-4- carboxamide 10

(S)-2-(3-oxo-3H-spiro [isobenzofuran-1,4′-piperidin]-1′-yl)-6-((2-oxopyrrolidin-3- yl)amino)pyrimidine-4- carboxamide 11

(S)-2-(4-oxo-1-phenyl-1,3,8- triazaspiro[4.5]decan-8-yl)-6-((2-oxopyrrolidin-3- yl)amino)pyrimidine-4- carboxamide

Further, the present disclosure also provides compounds presented inTABLE 2A, and pharmaceutically acceptable salts, solvates, hydrates,N-oxides, and diastereomers thereof.

TABLE 2A Cpd. No. Structure Name 12

8-(4-(4-fluorophenoxy)phenyl)- 1,3,8-triazaspiro[4.5]decane-2,4- dione13

8-(4-(3-fluorophenoxy)phenyl)- 1,3,8-triazaspiro[4.5]decane-2,4- dione14

8-(4-(3-(trifluoromethyl)phenoxy)- phenyl)-1,3,8-triazaspiro[4.5]decan-2,4-dione 15

8-(4-(4-(trifluoromethoxy)phenyl)- pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione 16

8-(5-(4-fluorophenoxy)pyridin-2- yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione 17

8-(5-(4-(trifluoromethyl)phenoxy)- pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione 18

8-(5-(3-(trifluoromethyl)phenoxy)- pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione 19

8-(4-(4-(trifluoromethyl)phenoxy)- phenyl)-1,3,8-triazaspiro-[4.5]decane-2,4-dione 20

8-(3-(4-fluorophenoxy)pyridin-2- yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione 21

8-(4-(3-(trifluoromethoxy)- phenyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione

As used herein, the term “alkyl” as used by itself or as part of anothergroup refers to a straight- or branched-chain aliphatic hydrocarboncontaining one to twelve carbon atoms (i.e., C₁₋₁₂ alkyl) or the numberof carbon atoms designated (i.e., a C₁ alkyl (such as, methyl), a C₂alkyl (such as, ethyl), a C₃ alkyl (such as, propyl or isopropyl, etc.).In one embodiment, the alkyl group is chosen from a straight chain C₁₋₁₀alkyl group. In another embodiment, the alkyl group is chosen from abranched chain C₃₋₁₀ alkyl group. In another embodiment, the alkyl groupis chosen from a straight chain C₁₋₆ alkyl group. In another embodiment,the alkyl group is chosen from a branched chain C₃₋₆ alkyl group. Inanother embodiment, the alkyl group is chosen from a straight chain C₁₋₄alkyl group. In another embodiment, the alkyl group is chosen from abranched chain C₃₋₄ alkyl group. In another embodiment, the alkyl groupis chosen from a straight or branched chain C₃₋₄ alkyl group.Non-limiting exemplary C₁₋₁₀ alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl, hexyl,heptyl, octyl, nonyl, decyl, and the like. Non-limiting exemplary C₁₋₄alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, and iso-butyl.

As used herein, the term “optionally substituted alkyl” as used byitself or as part of another group means that the alkyl as defined aboveis either unsubstituted or substituted with one, two, or threesubstituents independently chosen from amino, nitro, hydroxy,haloalkoxy, heterocyclo, aryloxy, aralkyloxy, alkylthio, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, cycloalkyl, carboxamido, and the like.In one embodiment, the optionally substituted alkyl is substituted withtwo substituents. In another embodiment, the optionally substitutedalkyl is substituted with one substituent. Non-limiting exemplaryoptionally substituted alkyl groups include —NH₂, —COOH, —OH,—CH₂CH₂NO₂, —CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh, —CH₂C₆H₁₁, —CONH₂,and the like.

As used herein, the term “cycloalkyl” as used by itself or as part ofanother group refers to saturated and partially unsaturated (containingone or two double bonds) cyclic aliphatic hydrocarbons containing one tothree rings having from three to twelve carbon atoms (i.e., C₃₋₁₂cycloalkyl) or the number of carbons designated. In one embodiment, thecycloalkyl group is saturated. In one embodiment, the cycloalkyl grouphas two rings. In one embodiment, the cycloalkyl group has one ring. Inanother embodiment, the cycloalkyl group is chosen from a C₃₋₈cycloalkyl group. In another embodiment, the cycloalkyl group is chosenfrom a C₃₋₆ cycloalkyl group. Non-limiting exemplary cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbomyl, decalin, adamantyl, cyclohexenyl, and the like.

As used herein, the term “optionally substituted cycloalkyl” as used byitself or as part of another group means that the cycloalkyl as definedabove is either unsubstituted or substituted with one, two, or threesubstituents independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkyl is substituted with two substituents. In another embodiment,the optionally substituted cycloalkyl is substituted with onesubstituent. Non-limiting exemplary optionally substituted cycloalkylgroups include:

As used herein, the term “alkenyl” as used by itself or as part ofanother group refers to an alkyl group as defined above containing one,two or three carbon-to-carbon double bonds. In one embodiment, thealkenyl group is chosen from a C₂₋₆ alkenyl group. In anotherembodiment, the alkenyl group is chosen from a C₂₋₄ alkenyl group.Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

As used herein, the term “optionally substituted alkenyl” as used hereinby itself or as part of another group means the alkenyl as defined aboveis either unsubstituted or substituted with one, two or threesubstituents independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, or heterocyclo.

As used herein, the term “alkynyl” as used by itself or as part ofanother group refers to an alkyl group as defined above containing oneto three carbon-to-carbon triple bonds. In one embodiment, the alkynylhas one carbon-to-carbon triple bond. In one embodiment, the alkynylgroup is chosen from a C₂₋₆ alkynyl group. In another embodiment, thealkynyl group is chosen from a C₂₋₄ alkynyl group. Non-limitingexemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl,pentynyl, and hexynyl groups.

As used herein, the term “optionally substituted alkynyl” as used hereinby itself or as part of another group means the alkynyl as defined aboveis either unsubstituted or substituted with one, two or threesubstituents independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, or heterocyclo.

As used herein, the term “haloalkyl” as used by itself or as part ofanother group refers to an alkyl group substituted by one or morefluorine, chlorine, bromine and/or iodine atoms. In one embodiment, thealkyl group is substituted by one, two, or three fluorine and/orchlorine atoms. In another embodiment, the haloalkyl group is chosenfrom a C₁₋₄ haloalkyl group. Non-limiting exemplary haloalkyl groupsinclude fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl,1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.

As used herein, the term “hydroxyalkyl” as used by itself or as part ofanother group refers to an alkyl group substituted with one or more,e.g., one, two, or three, hydroxy groups. In one embodiment, thehydroxyalkyl group refers to a monohydroxyalkyl group, i.e., substitutedwith one hydroxy group. However, the hydroxyalkyl group as used in thepresent disclosure may also refer to an alkyl group substituted by twoor more hydroxy groups. That is, the hydroxyalkyl group used hereinincludes a dihydroxyalkyl group, i.e., substituted with two hydroxygroups. In one embodiment, the hydroxyalkyl group is chosen from a C₁₋₄hydroxyalkyl group. Non-limiting exemplary hydroxyalkyl groups includehydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, suchas 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl,3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl,2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

As used herein, the term “(carboxamido)(hydroxy)alkyl” as used by itselfor as part of another group refers to an alkyl group that is substitutedwith one or more hydroxy groups, and also with a carboxamido group.Non-limiting exemplary (carboxamido)(hydroxy)alkyl groups include—CH(OH)C(O)NH₂, —CH₂CH(OH)C(O)NH₂, —CH(OH)CH(OH)C(O)NH₂, and the like.

As used herein, the term “alkoxy” as used by itself or as part ofanother group refers to an optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted alkenyl or optionallysubstituted alkynyl attached to a terminal oxygen atom. In oneembodiment, the alkoxy group is chosen from a C₁₋₄ alkoxy group. Inanother embodiment, the alkoxy group is chosen from a C₁₋₄ alkylattached to a terminal oxygen atom, e.g., methoxy, ethoxy, andtert-butoxy.

As used herein, the term “alkylthio” as used by itself or as part ofanother group refers to a sulfur atom substituted by an optionallysubstituted alkyl group. In one embodiment, the alkylthio group ischosen from a C₁₋₄ alkylthio group. Non-limiting exemplary alkylthiogroups include —SCH₃, and —SCH₂CH₃.

As used herein, the term “alkoxyalkyl” as used by itself or as part ofanother group refers to an alkyl group substituted with an alkoxy group.Non-limiting exemplary alkoxyalkyl groups include methoxymethyl,methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl,ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl,propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl,isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.

As used herein, the term “heteroalkyl” as used by itself or part ofanother group refers to a stable straight or branched chain hydrocarbonradical containing 1 to 10 carbon atoms and at least two heteroatoms,which can be the same or different, selected from O, N, or S,wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally beoxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized.The heteroatoms can be placed at any interior position of theheteroalkyl group or at a position at which the heteroalkyl group isattached to the remainder of the molecule. In one embodiment, theheteroalkyl group contains two oxygen atoms. Non-limiting exemplaryheteroalkyl groups include —CH₂OCH—₂CH₂OCH₃, —OCH₂CH₂OCH₂CH₂OCH₃,—CH₂NHCH₂CH₂OCH₂, —OCH₂CH₂NH₂, and —NHCH₂CH₂N(H)CH₃.

As used herein, the term “haloalkoxy” as used by itself or as part ofanother group refers to a haloalkyl attached to a terminal oxygen atom.Non-limiting exemplary haloalkoxy groups include fluoromethoxy,difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.

As used herein, the term “aryl” as used by itself or as part of anothergroup refers to a monocyclic or bicyclic aromatic ring system havingfrom six to fourteen carbon atoms (i.e., C₆-C₁₄ aryl). Non-limitingexemplary aryl groups include phenyl (abbreviated as “Ph”), naphthyl,phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, andfluorenyl groups. In one embodiment, the aryl group is chosen fromphenyl or naphthyl.

As used herein, the term “optionally substituted aryl” as used herein byitself or as part of another group means that the aryl as defined aboveis either unsubstituted or substituted with one to five substituentsindependently chosen from halo, nitro, cyano, hydroxy, amino,alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy,aryloxy, heteroaryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl,(cycloalkylamino)alkyl, (C₁-C₄ haloalkoxy)alkyl, or (heteroaryl)alkyl.In one embodiment, the optionally substituted aryl is an optionallysubstituted phenyl. In one embodiment, the optionally substituted phenylhas four substituents. In another embodiment, the optionally substitutedphenyl has three substituents. In another embodiment, the optionallysubstituted phenyl has two substituents. In another embodiment, theoptionally substituted phenyl has one substituent. Non-limitingexemplary substituted aryl groups include 2-methylphenyl,2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl,3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,2-fluoro-3-chlorophenyl, and 3-chloro-4-fluorophenyl. The termoptionally substituted aryl is meant to include groups having fusedoptionally substituted cycloalkyl and fused optionally substitutedheterocyclo rings. Examples include:

As used herein, the term “aryloxy” as used by itself or as part ofanother group refers to an optionally substituted aryl attached to aterminal oxygen atom. A non-limiting exemplary aryloxy group is PhO—.

As used herein, the term “heteroaryloxy” as used by itself or as part ofanother group refers to an optionally substituted heteroaryl attached toa terminal oxygen atom. Non-limiting exemplary heteroaryloxy groupsinclude:

As used herein, the term “aralkyloxy” as used by itself or as part ofanother group refers to an aralkyl group attached to a terminal oxygenatom. A non-limiting exemplary aralkyloxy group is PhCH₂O—.

As used herein, the term “heteroaryl” or “heteroaromatic” refers tomonocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms(i.e., C₅-C₁₄ heteroaryl) and 1, 2, 3, or 4 heteroatoms independentlychosen from oxygen, nitrogen and sulfur. In one embodiment, theheteroaryl has three heteroatoms. In another embodiment, the heteroarylhas two heteroatoms. In another embodiment, the heteroaryl has oneheteroatom. In one embodiment, the heteroaryl is a C₅ heteroaryl. Inanother embodiment, the heteroaryl is a C₆ heteroaryl. Non-limitingexemplary heteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl(e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl),pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g.,2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g.,thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g.,isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl”is also meant to include possible N-oxides. Exemplary N-oxides includepyridyl N-oxide and the like.

As used herein, the term “optionally substituted heteroaryl” as used byitself or as part of another group means that the heteroaryl as definedabove is either unsubstituted or substituted with one to foursubstituents, e.g., one or two substituents, independently chosen fromhalo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo,alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl,(dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl,(heterocyclo)alkyl, and (heteroaryl)alkyl. In one embodiment, theoptionally substituted heteroaryl has one substituent. In oneembodiment, the optionally substituted is an optionally substitutedpyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogenatom can be substituted. In another embodiment, the optionallysubstituted heteroaryl is an optionally substituted indole.

As used herein, the term “heterocycle” or “heterocyclo” as used byitself or as part of another group refers to saturated and partiallyunsaturated (e.g., containing one or two double bonds) cyclic groupscontaining one, two, or three rings having from three to fourteen ringmembers (i.e., a 3- to 14-membered heterocyclo) and at least oneheteroatom. Each heteroatom is independently selected from the groupconsisting of oxygen, sulfur, including sulfoxide and sulfone, and/ornitrogen atoms, which can be quaternized. The term “heterocyclo” ismeant to include cyclic ureido groups such as 2-imidazolidinone andcyclic amide groups such as β-lactam, γ-lactam, δ-lactam and ε-lactam.The term “heterocyclo” is also meant to include groups having fusedoptionally substituted aryl groups, e.g., indolinyl. In one embodiment,the heterocyclo group is chosen from a 5- or 6-membered cyclic groupcontaining one ring and one or two oxygen and/or nitrogen atoms. Theheterocyclo can be optionally linked to the rest of the molecule througha carbon or nitrogen atom. Non-limiting exemplary heterocyclo groupsinclude 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl,morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.

As used herein, the term “optionally substituted heterocyclo” as usedherein by itself or part of another group means the heterocyclo asdefined above is either unsubstituted or substituted with one to foursubstituents independently selected from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl,(heteroaryl)alkyl, and the like. Substitution may occur on any availablecarbon or nitrogen atom, and may form a spirocycle. Non-limitingexemplary optionally substituted heterocyclo groups include:

As used herein, the term “amino” as used by itself or as part of anothergroup refers to —NH₂.

As used herein, the term “alkylamino” as used by itself or as part ofanother group refers to —NHR¹⁵, wherein R¹⁵ is alkyl.

As used herein, the term “dialkylamino” as used by itself or as part ofanother group refers to —NR^(16a)R^(16b), wherein R^(16a) and R^(16b)are each independently alkyl or R^(16a) and R^(16b) are taken togetherto form a 3- to 8-membered optionally substituted heterocyclo.

As used herein, the term “hydroxyalkylamino” as used by itself or aspart of another group refers to —NHR¹⁷, wherein R¹⁷ is hydroxyalkyl.

As used herein, the term “cycloalkylamino” as used by itself or as partof another group refers to —NR^(19a)R^(19b), wherein R^(19a) isoptionally substituted cycloalkyl and R^(19b) is hydrogen or alkyl.

As used herein, the term “(amino)alkyl” as used by itself or as part ofanother group refers to an alkyl group substituted with an amino group.Non-limiting exemplary amino alkyl groups include —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂ and the like.

As used herein, the term “(alkylamino)alkyl” as used by itself or aspart of another group refers to an alkyl group substituted with analkylamino group. A non-limiting exemplary (alkylamino)alkyl group is—CH₂CH₂N(H)CH₃.

As used herein, the term “(dialkylamino)alkyl” as used by itself or aspart of another group refers to an alkyl group substituted by adialkylamino group. A non-limiting exemplary (dialkylamino)alkyl groupis —CH₂CH₂N(CH₃)₂.

As used herein, the term “(cycloalkylamino)alkyl” as used by itself oras part of another group refers to an alkyl group substituted by acycloalkylamino group. Non-limiting exemplary (cycloalkylamino)alkylgroups include —CH₂N(H)cyclopropyl, CH₂N(H)cyclobutyl,—CH₂N(H)cyclohexyl, and the like.

As used herein, the term “((amino)alkyl)carbonyl” as used by itself oras part of another group refers to an (alkyl)carbonyl group (i.e.,—C(O)alkyl) substituted by an amino group (at the alkyl part). Further,the term “optionally-substituted ((amino)alkyl)carbonyl” refers to an((amino)alkyl)carbonyl group carrying one or more optional substituentsthat are attached to the alkyl part or to the amino part, or both.Suitable substituents include, such as, the above-defined suitablesubstituents for an alkyl group, and the above-defined suitablesubstituents for an amino group. Non-limiting exemplaryoptionally-substituted ((amino)alkyl)carbonyl groups include

and the like.

As used herein, the term “(C₁-C₄ haloalkoxy)alkyl” as used by itself oras part of another group refers to an alkyl group substituted by a C₁-C₄haloalkoxy group. Non-limiting exemplary (C₁-C₄ haloalkoxy)alkyl groupsinclude —CH₂OCH₂CF₃ and —CH₂OCF₃.

As used herein, the term “(cyano)alkyl” as used by itself or as part ofanother group refers to an alkyl group substituted with one or morecyano, e.g., —CN, groups. Non-limiting exemplary (cyano)alkyl groupsinclude —CH₂CH₂CN, —CH₂CH₂CH₂CN, and —CH₂CH₂CH₂CH₂CN.

As used herein, the term “carboxamido” as used by itself or as part ofanother group refers to a radical of formula —C(═O)NR^(24a)R^(24b),wherein R^(24a) and R^(24b) are each independently hydrogen, optionallysubstituted alkyl, optionally substituted aryl, or optionallysubstituted heteroaryl, or R^(24a) and R^(24b) taken together with thenitrogen to which they are attached form a 3- to 8-membered heterocyclogroup. In one embodiment, R^(24a) and R^(24b) are each independentlyhydrogen or optionally substituted alkyl. Non-limiting exemplarycarboxamido groups include —CONH₂, —CON(H)CH₃, CON(CH₃)₂, and CON(H)Ph.

As used herein, the term “(carboxamido)alkyl” as used by itself or aspart of another group refers to an alkyl group substituted with acarboxamido group. Non-limiting exemplary (carboxamido)alkyl groupsinclude —CH₂CONH₂, —C(H)CH₃—CONH₂, and —CH₂CON(H)CH₃.

As used herein, the term “sulfonamido” as used by itself or as part ofanother group refers to a radical of the formula —SO₂NR^(23a)R^(23b),wherein R^(23a) and R^(23b) are each independently hydrogen, optionallysubstituted alkyl, or optionally substituted aryl, or R^(23a) andR^(23b) taken together with the nitrogen to which they are attached forma 3- to 8-membered heterocyclo group. Non-limiting exemplary sulfonamidogroups include —SO₂NH₂, —SO₂N(H)CH₃, and —SO₂N(H)Ph.

As used herein, the term “alkylcarbonyl” as used by itself or as part ofanother group refers to a carbonyl group, i.e., —C(═O)—, substituted byan alkyl group. A non-limiting exemplary alkylcarbonyl group is —COCH₃.

As used herein, the term “arylcarbonyl” as used by itself or as part ofanother group refers to a carbonyl group, i.e., —C(═O)—, substituted byan optionally substituted aryl group. A non-limiting exemplaryarylcarbonyl group is —COPh.

As used herein, the term “alkylsulfonyl” as used by itself or as part ofanother group refers to a sulfonyl group, i.e., —SO₂—, substituted byany of the above-mentioned optionally substituted alkyl groups. Anon-limiting exemplary alkylsulfonyl group is —SO₂CH₃.

As used herein, the term “arylsulfonyl” as used by itself or as part ofanother group refers to a sulfonyl group, i.e., —SO₂—, substituted byany of the above-mentioned optionally substituted aryl groups. Anon-limiting exemplary arylsulfonyl group is —SO₂Ph.

As used herein, the term “mercaptoalkyl” as used by itself or as part ofanother group refers to any of the above-mentioned alkyl groupssubstituted by a —SH group.

As used herein, the term “carboxy” as used by itself or as part ofanother group refers to a radical of the formula —COOH.

As used herein, the term “carboxyalkyl” as used by itself or as part ofanother group refers to any of the above-mentioned alkyl groupssubstituted with a —COOH. A non-limiting exemplary carboxyalkyl group is—CH₂CO₂H.

As used herein, the term “aralkyl” as used by itself or as part ofanother group refers to an alkyl group substituted with one, two, orthree optionally substituted aryl groups. In one embodiment, the aralkylgroup is a C₁₋₄ alkyl substituted with one optionally substituted arylgroup. Non-limiting exemplary aralkyl groups include benzyl, phenethyl,—CHPh₂, and —CH(4-F-Ph)₂.

As used herein, the term “ureido” as used by itself or as part ofanother group refers to a radical of the formula—NR^(22a)—C(═O)—NR^(22b)R^(22c), wherein R^(22a) is hydrogen, alkyl, oroptionally substituted aryl, and R^(22b) and R^(22c) are eachindependently hydrogen, alkyl, or optionally substituted aryl, orR^(22b) and R^(22c) taken together with the nitrogen to which they areattached form a 4- to 8-membered heterocyclo group. Non-limitingexemplary ureido groups include —NH—C(C═O)—NH₂ and —NH—C(C═O)—NHCH₃.

As used herein, the term “guanidino” as used by itself or as part ofanother group refers to a radical of the formula—NR^(25a)—C(═NR¹⁴)—NR^(25b)R^(25c), wherein R^(25a), R^(25b), andR^(25c) are each independently hydrogen, alkyl, or optionallysubstituted aryl, and R¹⁴ is hydrogen, alkyl, cyano, alkylsulfonyl,alkylcarbonyl, carboxamido, or sulfonamido. Non-limiting exemplaryguanidino groups include —NH—C(C═NH)—NH₂, —NH—C(C═NCN)—NH₂,—NH—C(C═NH)—NHCH₃ and the like.

As used herein, the term “(heterocyclo)alkyl” as used by itself or aspart of another group refers to an alkyl group substituted with one,two, or three optionally substituted heterocyclo groups. In oneembodiment, the (heterocyclo)alkyl is a C₁₋₄ alkyl substituted with oneoptionally substituted heterocyclo group. Non-limiting exemplary(heterocyclo)alkyl groups include:

As used herein, the term “(heteroaryl)alkyl” as used by itself or aspart of another group refers to an alkyl group substituted with one,two, or three optionally substituted heteroaryl groups. In oneembodiment, the (heteroaryl)alkyl group is a C₁₋₄ alkyl substituted withone optionally substituted heteroaryl group. Non-limiting exemplary(heteroaryl)alkyl groups include:

Further, the present disclosure encompasses any of the Compounds of theDisclosure being isotopically-labelled (i.e., radiolabeled) by havingone or more atoms replaced by an atom having a different atomic mass ormass number. Examples of isotopes that can be incorporated into thedisclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively, e.g.,³H, ¹¹C, and ¹⁴C. Isotopically-labeled Compounds of the Disclosure canbe prepared by methods known in the art.

The present disclosure encompasses ³H, ¹¹C, or ¹⁴C radiolabeledCompounds of the Disclosure and the use of any such compounds asradioligands for their ability to bind to the sodium channel. Forexample, one use of the labeled compounds of the present disclosure isthe characterization of specific receptor binding. Another use of alabeled Compound of the Disclosure is an alternative to animal testingfor the evaluation of structure-activity relationships. For example, thereceptor assay can be performed at a fixed concentration of a labeledCompound of the Disclosure and at increasing concentrations of a testcompound in a competition assay. For example, a tritiated Compound ofthe Disclosure can be prepared by introducing tritium into theparticular compound, for example, by catalytic dehalogenation withtritium. This method may include reacting a suitably halogen-substitutedprecursor of the compound with tritium gas in the presence of a suitablecatalyst, for example, Pd/C, in the presence or absence of a base. Othersuitable methods for preparing tritiated compounds can be found inFiler, Isotopes in the Physical and Biomedical Sciences, Vol. 1, LabeledCompounds (Part A), Chapter 6 (1987). ¹⁴C-labeled compounds can beprepared by employing starting materials having a ¹⁴C carbon.

Some of the Compounds of the Disclosure may contain one or moreasymmetric centers and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms. The present disclosure is meant toencompass the use of all such possible forms, as well as their racemicand resolved forms and mixtures thereof. The individual enantiomers canbe separated according to methods known in the art in view of thepresent disclosure. When the compounds described herein contain olefinicdouble bonds or other centers of geometric asymmetry, and unlessspecified otherwise, it is intended that they include both E and Zgeometric isomers. All tautomers are intended to be encompassed by thepresent disclosure as well.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule.

The terms “a” and “an” refer to one or more.

The term “treat,” “treating” or “treatment” is meant to encompassadministering to a subject a compound of the present disclosure for thepurposes of amelioration or cure, including preemptive and palliativetreatment. In one embodiment, the term “treat,” “treating” or“treatment” is meant to encompass administering to a subject a compoundof the present disclosure for the purposes of amelioration or cure.

The term “about,” as used herein in connection with a measured quantity,refers to the normal variations in that measured quantity, as expectedby the skilled artisan making the measurement and exercising a level ofcare commensurate with the objective of measurement and the precision ofthe measuring equipment.

The present disclosure encompasses the preparation and use of salts ofthe Compounds of the Disclosure, including non-toxic pharmaceuticallyacceptable salts. Examples of pharmaceutically acceptable addition saltsinclude inorganic and organic acid addition salts and basic salts. Thepharmaceutically acceptable salts include, but are not limited to, metalsalts such as sodium salt, potassium salt, cesium salt and the like;alkaline earth metals such as calcium salt, magnesium salt and the like;organic amine salts such as triethylamine salt, pyridine salt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, phosphate, sulphate and the like;organic acid salts such as citrate, lactate, tartrate, maleate,fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,oxalate, formate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate and the like; and amino acid saltssuch as arginate, asparginate, glutamate and the like.

Acid addition salts can be formed by mixing a solution of the particularCompound of the Disclosure with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present disclosure with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The present disclosure encompasses the preparation and use of solvatesof Compounds of the Disclosure. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present disclosure with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present disclosure is about 2:1, about 1:1or about 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of the Disclosure can be present assolvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, ethanol, and the like, and it is intended that thedisclosure includes both solvated and unsolvated forms of Compounds ofthe Disclosure. One type of solvate is a hydrate. A “hydrate” relates toa particular subgroup of solvates where the solvent molecule is water.Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a Compound of the Disclosure in a desired solvent(organic, water, or a mixture thereof) at temperatures above 20° C. toabout 25° C., then cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques such as infrared spectroscopy can be used toconfirm the presence of the solvent in a crystal of the solvate.

Since Compounds of the Disclosure are blockers of sodium (Na⁺) channels,a number of diseases and conditions mediated by sodium ion influx can betreated by employing these compounds. The present disclosure is thusdirected generally to a method for treating a disorder responsive to theblockade of sodium channels in an animal suffering from, or at risk ofsuffering from, said disorder, said method comprising administering tothe animal an effective amount of one or more Compounds of theDisclosure.

The present disclosure is further directed to a method of modulatingsodium channels in an animal in need thereof, said method comprisingadministering to the animal a modulating-effective amount of at leastone Compound of the Disclosure.

More specifically, the present disclosure provides a method of treatingstroke, neuronal damage resulting from head trauma, epilepsy, neuronalloss following global and focal ischemia, pain (e.g., acute pain,chronic pain, which includes but is not limited to neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain), aneurodegenerative disorder (e.g., Alzheimer's disease, amyotrophiclateral sclerosis (ALS), or Parkinson's disease), migraine, manicdepression, tinnitus, myotonia, a movement disorder, or cardiacarrhythmia, or providing local anesthesia. In one embodiment, thedisclosure provides a method of treating pain. In another embodiment,the type of pain is chronic pain. In another embodiment, the type ofpain is neuropathic pain. In another embodiment, the type of pain ispostoperative pain. In another embodiment, the type of pain isinflammatory pain. In another embodiment, the type of pain is surgicalpain. In another embodiment, the type of pain is acute pain. In anotherembodiment, the treatment of pain (e.g., chronic pain, such asneuropathic pain, postoperative pain, or inflammatory pain, acute painor surgical pain) is preemptive. In another embodiment, the treatment ofpain is palliative. In each instance, such method of treatment requiresadministering to an animal in need of such treatment an amount of aCompound of the Disclosure that is therapeutically effective inachieving said treatment. In one embodiment, the amount of such compoundis the amount that is effective to block sodium channels in vitro. Inone embodiment, the amount of such compound is the amount that iseffective to block sodium channels in vivo.

Chronic pain includes, but is not limited to, inflammatory pain,postoperative pain, cancer pain, osteoarthritis pain associated withmetastatic cancer, trigeminal neuralgia, acute herpetic and postherpeticneuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion,occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout,phantom limb pain, burn pain, and other forms of neuralgia, neuropathic,and idiopathic pain syndromes.

Chronic somatic pain generally results from inflammatory responses totissue injury such as nerve entrapment, surgical procedures, cancer orarthritis (Brower, Nature Biotechnology 18:387-391 (2000)).

The inflammatory process is a complex series of biochemical and cellularevents activated in response to tissue injury or the presence of foreignsubstances (Levine, Inflammatory Pain, In: Textbook of Pain, Wall andMelzack eds., 3^(rd) ed., 1994). Inflammation often occurs at the siteof injured tissue, or foreign material, and contributes to the processof tissue repair and healing. The cardinal signs of inflammation includeerythema (redness), heat, edema (swelling), pain and loss of function(ibid.). The majority of patients with inflammatory pain do notexperience pain continually, but rather experience enhanced pain whenthe inflamed site is moved or touched. Inflammatory pain includes, butis not limited to, that associated with osteoarthritis and rheumatoidarthritis.

Chronic neuropathic pain is a heterogeneous disease state with anunclear etiology. In chronic neuropathic pain, the pain can be mediatedby multiple mechanisms. This type of pain generally arises from injuryto the peripheral or central nervous tissue. The syndromes include painassociated with spinal cord injury, multiple sclerosis, post-herpeticneuralgia, trigeminal neuralgia, phantom pain, causalgia, and reflexsympathetic dystrophy and lower back pain. Chronic pain is differentfrom acute pain in that patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia or by heat-, cold-, or mechano-allodynia.

Neuropathic pain can be caused by injury or infection of peripheralsensory nerves. It includes, but is not limited to, pain from peripheralnerve trauma, herpes virus infection, diabetes mellitus, causalgia,plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathicpain is also caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Stroke (spinal or brain) and spinal cord injury can alsoinduce neuropathic pain. Cancer-related neuropathic pain results fromtumor growth compression of adjacent nerves, brain, or spinal cord. Inaddition, cancer treatments, including chemotherapy and radiationtherapy, can also cause nerve injury. Neuropathic pain includes but isnot limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The present disclosure is also directed to the use of a Compound of theDisclosure in the manufacture of a medicament for treating a disorderresponsive to the blockade of sodium channels (e.g., any of thedisorders listed above) in an animal suffering from said disorder.

General Synthesis of Compounds

Compounds of the Disclosure are prepared using methods known to thoseskilled in the art in view of this disclosure, or by the illustrativemethod shown in the General Schemes below. In General Schemes 1-3, R¹,R^(5b), R⁶, R⁷, R⁹, and/or Z of Formulae AA-LL are as defined inconnection with Formula I, unless otherwise indicated. In GeneralSchemes 4 and 5, R¹, R^(5b), and E of Formulae M-T are as defined inconnection with Formula I, unless otherwise indicated.

Compound AA is converted to Compound CC by coupling with a suitableamine (such as, Compound BB) in the presence of a suitable couplingreagent (such as, HATU) and a suitable base (such as, DIPEA) in asuitable solvent (such as, DMF).

In the alternative, conversion of Compound AA to an acid chloride with asuitable reagent such as POCl₃ followed by reaction with Compound BB inthe presence of a suitable base (such as, DIPEA) in a suitable solvent(such as, DCM or Et₂O) gives Compound CC. Compound CC is converted toCompound EE by reaction with Compound DD in the presence of a suitablebase (such as, DIPEA) in a suitable solvent (such as, CAN). Compound EEis converted to Compound GG by reaction with Compound FF in the presenceof a suitable base (such as, K₂CO₃) in a suitable solvent (such as,DMF).

In a manner similar to that described in General Scheme 1, Compound AAis converted to Compound KK by coupling with a suitable alcohol such asCompound HH (wherein R is an alkyl group) followed by coupling withCompound DD and Compound FF.

Compound KK is converted to Compound LL by treatment with a suitablebase (such as, NaOH) in a suitable solvent (such as, aq. MeOH).

Compound M is converted to Compound O by coupling with a suitable boronreagent (such as, Compound N, wherein R is hydroxy, alkoxy, or amino) inthe presence of a suitable catalyst (such as, Pd(dppf)Cl₂) in a suitablesolvent (such as, THF). Compound O is converted to Compound P byreaction with Compound FF in the presence of a suitable base (such as,K₂CO₃) in a suitable solvent (such as, DMF).

Compound P is then converted to Compound Q by reacting with a suitableoxidizing agent (such as, OsO₄) with or without a co-oxidant (such as,NMO) in a suitable solvent (such as, aqueous acetone or alcohol). Suchoxidation can be effected in a chiral fashion by reaction of Compound Pwith a suitable chiral oxidizing agent (such as, AD-mix-alpha or beta)in a suitable solvent (such as, aqueous acetone or alcohol).

Compound P can also be converted to Compound R by reaction with asuitable reagent (such as, borane) in a suitable solvent (such as, THF)followed by reaction with a suitable oxidizing reagent (such as,hydrogen peroxide) in the presence of a suitable base (such as, NaOH) ina suitable solvent (such as, water).

Compound P is converted to Compound S by reaction with a suitableoxidizing agent (such as, OsO₄) in the presence of a suitable co-oxidant(such as, sodium periodate) in a suitable solvent (such as, aqueousTHF).

Compound S can also be prepared from Compound Q by oxidation with asuitable reagent (such as, sodium periodate) in a suitable solvent (suchas, aqueous THF). Compound S is converted to Compound T by reaction witha suitable reducing agent (such as, NaBH₄) in a suitable solvent (suchas, MeOH).

Compound U is converted to Compound W according to literature procedures(e.g., J. Med. Chem. 2008, 51, 2845) by reaction with Compound V using asuitable reagent (such as, 2,2,6,6-tetramethyl-3,5-heptanedione) in thepresence of a suitable base (such as, Cs₂CO₃) in the presence of asuitable Lewis acid, such as, copper (I) chloride (CuCl), in a suitablesolvent (such as, NMP).

Compound Y is converted to Compound Z according to literature proceduresdescribed in WO 2009044160 A1 by reaction with a suitable boron reagent(such as, Compound X) in the presence of a suitable base (such as, TEA)in a suitable solvent (such as, DCM).

Compound AA′ is converted to Compound AB according to literatureprocedures (as those described in Bioorganic & Medicinal ChemistryLetters, 2013, 23(24), 6777-6783) by reaction with a suitable boronreagent (such as, Compound X) in the presence of a suitable catalyst(such as, Pd(Ph₃P)₂Cl₂) in the presence of a suitable base (such as,TEA) in a suitable solvent (such as, DMF).

Compound AC is converted to Compound AE by reaction with Compound AD inthe presence of a suitable alcohol (such as, t-BuOH) in a suitablesolvent (such as, toluene). Removal of the protecting group in CompoundAE is achieved according to literature procedure (e.g. Greene, T. W.“Protective Groups in Organic Synthesis”, J. Wiley & Sons, N Y, 1981) togive Compound AF, which is further treated with a suitable base (suchas, ammonium carbonate) in a suitable solvent (such as, EtOH) followedby treatment with potassium cyanide and water to afford Compound AG.

Testing of Compounds

Compounds of the Disclosure were assessed by sodium mobilization and/orelectrophysiological assays for sodium channel blocker activity. Oneaspect of the present disclosure is based on the use of the Compounds ofthe Disclosure as sodium channel blockers. Based upon this property,Compounds of the Disclosure are considered useful in treating acondition or disorder responsive to the blockade of sodium ion channels,e.g., stroke, neuronal damage resulting from head trauma, epilepsy,seizures, general epilepsy with febrile seizures, severe myoclonicepilepsy in infancy, neuronal loss following global and focal ischemia,migraine, familial primary erythromelalgia, paroxysmal extreme paindisorder, cerebellar atrophy, ataxia, dystonia, tremor, mentalretardation, autism, a neurodegenerative disorder (e.g., Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), or Parkinson's disease),manic depression, tinnitus, myotonia, a movement disorder, cardiacarrhythmia, or providing local anesthesia. Compounds of the Disclosureare also expected to be effective in treating pain, e.g., acute pain,chronic pain, which includes but is not limited to, neuropathic pain,postoperative pain, and inflammatory pain, or surgical pain.

More specifically, the present disclosure is directed to Compounds ofthe Disclosure that are blockers of sodium channels. According to thepresent disclosure, those compounds having useful sodium channelblocking properties exhibit an IC₅₀ for Na_(v)1.1, Na_(v)1.2, Na_(v)1.3,Na_(v)1.4, Na_(v)1.5, Na_(v)1.6, Na_(v)1.7, Na_(v)1.8, and/or Na_(v)1.9of about 100 μM or less, e.g., about 50 μM or less, about 25 μM or less,about 10 μM or less, about 5 μM or less, or about 1 μM or less, insodium mobilization and/or electrophysiological assays. In certainembodiments, Compounds of the Disclosure exhibit an IC₅₀ for Na_(v)1.7of 100 μM or less, about 50 μM or less, about 25 μM or less, about 10 μMor less, about 5 μM or less, about 1 μM or less, about 0.5 μM or less,about 0.1 μM or less, about 0.05 μM or less, or about 0.01 μM or less.Compounds of the Disclosure can be tested for their Na⁺ channel blockingactivity using methods known in the art and by the followingfluorescence imaging and electrophysiological in vitro assays and/or invivo assays.

In one embodiment, Compounds of the Disclosure demonstrate substantiallyno penetration across the CNS blood-brain barrier in a mammal. Suchcompounds are referred to as “peripherally restricted” as a means todesignate their PNS versus CNS tissue selectivity.

In one embodiment, the PNS:CNS concentration ratio of a peripherallyrestricted Compound of the Disclosure is about 5:1, about 10:1, about20:1, about 30:1; about 50:1; about 100:1, about 250:1, about 500:1,about 1000:1, about 5,000:1, about 10,000:1, or more. Compounds of theDisclosure can be tested for their ability to penetrate the centralnervous system using in vitro and in vivo methods known in the art.

In Vitro Assay Protocols FLIPR® Assays

Recombinant Na_(v)1.7 Cell Line:

In vitro assays were performed in a recombinant cell line expressingcDNA encoding the alpha subunit (Na_(v)1.7, SCN9a, PN1, NE) of humanNa_(v)1.7 (Accession No. NM_002977). The cell line was provided byinvestigators at Yale University (Cummins et al, J. Neurosci. 18(23):9607-9619 (1998)). For dominant selection of the Na_(v)1.7-expressingclones, the expression plasmid co-expressed the neomycin resistancegene. The cell line was constructed in the human embryonic kidney cellline, HEK293, under the influence of the CMV major late promoter, andstable clones were selected using limiting dilution cloning andantibiotic selection using the neomycin analogue, G418. Recombinant betaand gamma subunits were not introduced into this cell line. Additionalcell lines expressing recombinant Na_(v)1.7 cloned from other speciescan also be used, alone or in combination with various beta subunits,gamma subunits or chaperones.

Non-Recombinant Cell Lines Expressing Native Na_(v)1.7:

Alternatively, in vitro assays can be performed in a cell lineexpressing native, non-recombinant Na_(v)1.7, such as the ND7 mouseneuroblastoma X rat dorsal root ganglion (DRG) hybrid cell line ND7/23,available from the European Cell Culture Collection (Cat. No. 92090903,Salisbury, Wiltshire, United Kingdom). The assays can also be performedin other cell lines expressing native, non-recombinant Na_(v)1.7, fromvarious species, or in cultures of fresh or preserved sensory neurons,such as dorsal root ganglion (DRG) cells, isolated from various species.Primary screens or counter-screens of other voltage-gated sodiumchannels can also be performed, and the cell lines can be constructedusing methods known in the art, purchased from collaborators orcommercial establishments, and they can express either recombinant ornative channels. The primary counter-screen is for one of the centralneuronal sodium channels, Na_(v)1.2 (rBIIa), expressed in HEK293 hostcells (Ilyin et al., Br. J. Pharmacol. 144:801-812 (2005)).Pharmacological profiling for these counter-screens is carried out underconditions similar to the primary or alternative Na_(v)1.7 assaysdescribed below.

Cell Maintenance:

Unless otherwise noted, cell culture reagents were purchased fromMediatech of Herndon, Va. The recombinant Na_(v)1.7/HEK293 cells wereroutinely cultured in growth medium consisting of Dulbecco's minimumessential medium containing 10% fetal bovine serum (FBS, Hyclone, ThermoFisher Scientific, Logan, Utah), 100 U/mL penicillin, 100 μg/mLstreptomycin, 2-4 mM L-glutamine, and 500 mg/mL G418. For natural,non-recombinant cell lines, the selective antibiotic was omitted, andadditional media formulations can be applied as needed.

Assay Buffer:

The assay buffer was formulated by removing 120 mL from a 1 L bottle offresh, sterile dH₂O (Mediatech, Herndon, Va.) and adding 100 mL of10×HBSS that does not contain Ca⁺⁺ or Mg⁺⁺ (Gibco, Invitrogen, GrandIsland, N.Y.) followed by 20 mL of 1.0 M Hepes, pH 7.3 (FisherScientific, BP299-100). The final buffer consisted of 20 mM Hepes, pH7.3, 1.261 mM CaCl₂, 0.493 mM MgCl₂, 0.407 mM Mg(SO)₄, 5.33 mM KCl,0.441 mM KH₂PO₄, 137 mM NaCl, 0.336 mM Na₂HPO₄ and 0.556 mM D-glucose(Hanks et al., Proc. Soc. Exp. Biol. Med. 71:196 (1949)), and the simpleformulation was typically the basic buffer throughout the assay (i.e.,all wash and addition steps).

CoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay:

The fluorescence indicator used in the primary fluorescence assay wasthe cell permeant version of CoroNa™ Green (Invitrogen, MolecularProbes, Eugene, Oreg.), a dye that emits light in the fluorescence range(Harootunian et al., J. Biol. Chem. 264(32):19458-19467 (1989)). Theintensity of this emission, but not the wavelength range, is increasedwhen the dye is exposed to Na⁺ ions, which it can bind with partialselectivity. Cells expressing Na_(v)1.7 or other sodium channels wereloaded with the CoroNa™ Green dye immediately in advance of thefluorescence assay, and then, after agonist stimulation, themobilization of Na⁺ ions was detected as the Na⁺ ions flowed from theextracellular fluid into the cytoplasm through the activated sodiumchannel pores. The dye was stored in the dark as a lyophilized powder,and then an aliquot was dissolved immediately before the cell loadingprocedure, according to the instructions of the manufacturer, to a stockconcentration of 10 mM in DMSO. It was then diluted in the assay bufferto a 4× concentrated working solution, so that the final concentrationof dye in the cell loading buffer was 5 μM.

Membrane Potential Dye for Alternative Fluorescence Assays:

A fluorescence indicator that can be used in alternative fluorescenceassays is the blue version membrane potential dye (MDS, MolecularDevices, Sunnyvale, Calif.), a dye that detects changes in moleculesfollowing a change in membrane potential. An increase in fluorescence isexpected if agonist stimulation provokes a change in membrane potential.Cells expressing Na_(v)1.7 or other sodium channels are incubated withthe membrane potential dye 30-60 minutes before the fluorescence assay.In the case of the KCl pre-stimulation version of the assay, the dye andall other components are washed out immediately before the assay, andthe dye is then replaced. In the version lacking KCl pre-stimulation,the dye remains on the cells and is not washed out or replaced. The dyeis stored in the dark as a lyophilized powder, and then an aliquotdissolved in assay buffer to form a 20×-concentrated stock solution thatcan be used for several weeks.

Agonists:

In the fluorescence assays, two agonists were used in combination,namely 1) veratridine; and 2) the venom from the yellow scorpion,Leiurus quinquestriatus hebraeus. Veratridine is an alkaloid smallmolecule that facilitates the capture of channel openings by inhibitinginactivation, and the scorpion venom is a natural preparation thatincludes peptide toxins selective for different subsets of voltage-gatedsodium channels. These scorpion toxins inhibit the fast inactivation oftheir cognate target channels. Stock solutions of the agonists wereprepared to 40 mM in DMSO (veratridine) and 1 mg/mL in dH₂O (scorpionvenom), and then diluted to make a 4× or 2× stock (depending on theparticular assay) in assay buffer, the final concentration being 100 μM(veratridine) and 10 μg/mL (scorpion venom). Both of the agonists werepurchased from Sigma Aldrich, St. Louis, Mo.

Test Compounds:

Test compounds were dissolved in DMSO to yield 10 mM stock solutions.The stock solutions were further diluted using DMSO in 1:3 serialdilution steps with 10 points (10,000 μM, 3.333 μM, 1.111 μM, 370 μM,123 μM, 41 μM, 14 μM, 4.6 μM, 1.5 μM and 0.5 μM). The stock solutionswere further diluted in assay buffer (1:125) as 4× stock serialdilutions with a DMSO concentration of 0.8% (final [DMSO], in the assay,from the compounds component=0.2%), so that the compounds' finalconcentrations in the assay were 20 μM, 6.7 μM, 2.2 μM, 0.74 μM, 0.25 μMand 0.08 μM, 0.03 μM, 0.01 μM, 0.003 μM and 0.001 μM. If a particulartest article appeared to be especially potent, then the concentrationcurve was adjusted, e.g., to 10-fold lower concentrations, in order toperform the dose-response in a more relevant concentration range.Compound dilutions were added during the dye-loading and pre-stimulationstep, and then again during the fluorescence assay, early in the kineticread. Compound dilutions were added in duplicate rows across the middle80 wells of the 96-well plate, whereas the fully stimulated and thefully inhibited controls (positive and negative) were located in the top4 side wells and the bottom 4 side wells, respectively, on the left andright sides of the assay plate.

Data Analysis:

The data were analyzed according to methods known to those skilled inthe art or using the GraphPad® Prism Program, version 4.0 or higher(available from GraphPad Software, San Diego, Calif.) to determine theIC₅₀ value for the test article. At least one standard referencecompound was evaluated during each experiment.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay with KCl and Test ArticlePre-Incubation:

Cells were prepared by plating the recombinant HEK293 cells or otherhost cells expressing either recombinant or non-recombinant, native,Na_(v)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately fewer cells andless media. The plate was then incubated in growth media, with orwithout selective antibiotic, overnight at 37° C. at 5% CO₂, 95%humidity, in preparation for the assay. For counter-screens of othervoltage-gated sodium channels, the procedure was very similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or isoform.

The next day, at the start of the assay, the media was flicked from thecells and the wells were washed once with 50 μl/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles,CoroNa™ Green AM sodium dye (for cell loading) and KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents were added as follows, immediately after the wash step: 1)first, the compound dilutions and controls were added as 4× concentratesin assay buffer at 50 μL/well; 2) CoroNa™ Green AM dye was diluted fromthe stock solution to 20 μM in assay buffer (4× concentrate) and addedto the plate at 50 μL/well; and 3) finally, a solution of 180 mM KCl(2×) was prepared by diluting a 2M stock solution into assay buffer andthe solution was added to the cells at 100 μl/well. The cells wereincubated at 25° C. in the dark for 30 min. before their fluorescencewas measured. The plates containing dye-loaded cells were then flickedto remove the pre-incubation components and washed once with 100 μL/wellassay buffer. A 100 μL/well aliquot of assay buffer was added back tothe plate, and the real-time assay was commenced. The fluorescence ofcells was measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.) Samples wereexcited by either a laser or a PMT light source (Excitationwavelength=470-495 nM) and the emissions are filtered (Emissionwavelength=515-575 nM). The additions of compound and the channelactivators in this cell-based, medium-to-high throughput assay wereperformed on the fluorescence plate reader and the results (expressed asrelative fluorescence units) were captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, therewas a 15 sec. base line, with camera shots taken every 1.5 sec., thenthe test compounds were added, then another 120 sec. baseline wasconducted, with camera shots taken every 3 sec.; and finally, theagonist solution (containing veratridine and scorpion venom) was added.The amplitude of fluorescence increase, resulting from the binding ofNa⁺ ions to the CoroNa™ Green dye, was captured for ˜180 sec.thereafter. Results were expressed in relative fluorescence units (RFU)and can be determined by using the maximum signal during the latter partof the stimulation; or the maximum minus the minimum during the wholeagonist stimulation period; or by taking the area under the curve forthe whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen were typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gated sodium channels or otherbiologically relevant target molecules.

FLIPR® or FLIPR^(TETRA)® Membrane Potential Assay with KCl and TestArticle Pre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(V)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay (see, e.g., Benjamin et. al., J. Biomol.Screen 10(4):365-373 (2005)). For screens and counter-screens of othervoltage-gated sodium channels, the assay protocol is similar, thoughoptimal densities of cells, media and subsequent assay components can befine-tuned for the particular cell line or sodium channel isoform beingtested.

The next day, at the start of the assay, the media is flicked from thecells and the wells are washed once with 50 μL/well assay buffer (1×Hank's balanced salt solution without sodium bicarbonate or phenol red,20 mM Hepes, pH 7.3) and then pre-incubated with the test articles, themembrane potential dye (for cell loading), and the KCl forre-polarization and synchronization of the channels in the entirepopulation of cells. For this dye-loading and pre-stimulation step, thecomponents are added as follows, immediately after the wash step: 1)first, the compound dilutions and controls are added as 4× concentratesin assay buffer at 50 μL/well; 2) membrane potential dye is diluted fromthe stock solution in assay buffer (4× concentrate) and added to theplate at 50 μL/well; and 3) finally, a solution of 180 mM KCl (2×) isprepared by diluting a 2M stock solution into assay buffer and thesolution added to the cells at 100 μL/well. The cells are incubated at37° C. in the dark for 30-60 min. before their fluorescence is measured.

The plates containing dye-loaded cells are then flicked to remove thepre-incubation components and washed once with 50 μL/well assay buffer.A 50 μL/well aliquot of membrane potential dye is added back to theplate, and the real-time assay is commenced. The fluorescence of cellsis measured using a fluorescence plate reader (FLIPR^(TETRA)® orFLIPR384®, MDS, Molecular Devices, Sunnyvale, Calif.). Samples areexcited by either a laser or a PMT light source (Excitationwavelength=510-545 nM) and the emissions are filtered (Emissionwavelength=565-625 nM). The additions of the compounds (first) and thenthe channel activators (later) in this are performed on the fluorescenceplate reader and the results, expressed as relative fluorescence units(RFU), are captured by means of camera shots every 1-3 sec., thendisplayed in real-time and stored. Generally, there is a 15 sec. baseline, with camera shots taken every 1.5 sec., then the test compoundsare added, then another 120 sec. baseline is conducted, with camerashots taken every 3 sec.; and finally, the agonist solution (containingveratridine and scorpion venom) is added. The amplitude of fluorescenceincrease, resulting from the detection of membrane potential change, iscaptured for ˜120 sec. thereafter. Results are expressed in relativefluorescence units (RFU) and can be determined by using the maximumsignal during the latter part of the stimulation; or the maximum minusthe minimum during the whole stimulation period; or by taking the areaunder the curve for the whole stimulation period.

The assay can be performed as a screening assay as well with the testarticles present in standard amounts (e.g., 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

FLIPR® or FLIPR^(TETRA)® Sodium Dye Assay without KCl and Test ArticlePre-Incubation:

Cells are prepared by plating the recombinant HEK293 cells or other hostcells expressing either recombinant or non-recombinant, native,Na_(V)1.7 alpha subunit, alone or in combination with various beta andgamma subunits at a density of ˜40,000 cells/well into a 96-well black,clear-bottom, PDL-coated plate. The assay can be adapted to 384-well or1,536-well format, if desired, using proportionately less cells andmedia. The plate is then incubated in growth media, with or withoutselective antibiotic, overnight at 37° C. at 5% CO₂, 95% humidity, inpreparation for the assay. For counter-screens of other voltage-gatedsodium channels, the procedure is very similar, though optimal densitiesof cells, media and subsequent assay components can be fine-tuned forthe particular cell line or isoform.

The next day, at the start of the assay, the media is flicked from thecells and the wells washed once with 50 μL/well assay buffer (1× Hank'sbalanced salt solution without sodium bicarbonate or phenol red, 20 mMHepes, pH 7.3). Membrane potential dye is then added to each well of the96-well plate (50 μL/well), from a freshly diluted sample of the stock(now at 4× concentration) in the assay buffer. The cells are incubatedat 37° C. in the dark for 30-60 min. before their fluorescence ismeasured.

In this standard membrane potential assay, the 96-well plate containingdye-loaded cells is then loaded directly onto the plate reader withoutaspirating the dye solution and without any further washing of thecells. The fluorescence of cells is measured using a fluorescence platereader (FLIPR^(TETRA)® or FLIPR384®, MDS, Molecular Devices, Sunnyvale,Calif.). Samples are excited by either a laser or a PMT light source(Excitation wavelength=510-545 nM) and the emissions are filtered(Emission wavelength=565-625 nM). The additions of the compounds (first,50 μL/well from a 4× stock plate) and then the channel activators(later, 100 μL/well from a 2× stock solution) in this kinetic assay areperformed on the fluorescence plate reader and the results, expressed asrelative fluorescence units (RFU), are captured by means of camera shotsevery 1-3 sec., then displayed in real-time and stored. Generally, thereis a 15 sec. base line, with camera shots taken every 1.5 sec., then thetest compounds are added, then another 120 sec. baseline is conducted,with camera shots taken every 3 sec.; and finally, the agonist solution(containing veratridine and scorpion venom) is added. The amplitude offluorescence increase, resulting from the detection of membranepotential change, is captured for ˜120 sec. thereafter. Results areexpressed in relative fluorescence units (RFU) and can be determined byusing the maximum signal during the latter part of the stimulation; orthe maximum minus the minimum during the whole stimulation period; or bytaking the area under the curve for the whole stimulation period.

The assay can be performed as a screening assay as well, with the testarticles present in standard amounts (e.g. 10 μM) in only one or twowells of a multi-well plate during the primary screen. Hits in thisscreen are typically profiled more exhaustively (multiple times),subjected to dose-response or competition assays and tested in counterscreens against other voltage-gate sodium channels or other biologicallyrelevant target molecules.

Electrophysiology Assay

Cells Manual Electrophysiology:

The hNa_(v)1.7 expressing HEK-293 cells are plated on 35 mm culturedishes pre-coated with poly-D-lysine in standard DMEM culture media(Mediatech, Inc., Herndon, Va.) and incubated in a 5% CO₂ incubator at37° C. Cultured cells are used approximately 12-48 hours after plating.

Cells Automated Electrophysiology:

The hNa_(v)1.7 expressing HEK-293 cells are plated on tissue cultureflasks in standard DMEM culture media (Mediatech, Inc.) and incubated ina 5% CO₂ incubator at 37° C. Cultured cells are used approximately 12-48hours after plating.

Manual Electrophysiology:

On the day of experimentation, the 35 mm dish is placed on the stage ofan inverted microscope equipped with a perfusion system thatcontinuously perfuses the culture dish with fresh recording media. Agravity driven superfusion system is used to apply test solutionsdirectly to the cell under evaluation. This “shooter” system consists ofan array of glass pipettes connected to a motorized horizontaltranslator. The outlet of the shooter is positioned approximately 100 mfrom the cell of interest.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Axopatch 200B amplifier (Axon Instruments, FosterCity Calif.), 1322A A/D converter (Axon Instruments) and pClamp software(v. 8; Axon Instruments) and stored on a personal computer. Gigasealsare formed and the whole-cell configuration is established in voltageclamp mode, and membrane currents generated by hNa_(v)1.7 channels arerecorded. Borosilicate glass pipettes with resistance values between 1.5and 2.0 MΩ when filled with pipette solution are used and seriesresistance (<5 MΩ) is compensated by 75-80%. Signals are sampled at 50kHz and low pass filtered at 3 kHz.

Automated Electrophysiology:

On the day of experimentation, cells are prepared by removing media anddigesting with appropriate enzymes to suspend cells in externalsolution.

Whole cell currents are recorded using the whole-cell patch clampconfiguration using an Patchliner (Nanion Technologies, Munich Germany),EPC 10 quadro amplifiers (HEKA, Bellmore, N.Y.) and PatchControl HT10905 (Nanion Technologies) and PatchMaster v2×73 software (HEKA) andstored on a personal computer. Gigaseals are formed and the whole-cellconfiguration is established in voltage clamp mode, and membranecurrents generated by hNa_(v)1.7 are recorded. NPC-16 chips haveresistance values between 1.0 and 2.0 MΩ when filled with pipettesolution and series resistance (<5 MΩ). Signals are sampled at 25 kHzand low pass filtered at 3 kHz.

Voltage Protocols Manual Electrophysiology:

After establishing the whole-cell configuration in voltage clamp mode,voltage protocols are run to establish the 1) test potential (V_(max)),2) holding potential (V_(h)), and 3) the conditioning potential for eachcell.

After establishing the whole-cell configuration in voltage clamp mode, astandard I-V protocol is run to determine the potential at which themaximal current (I_(max)) is elicited. This potential is the testpotential (V_(t)). To determine a conditioning potential at which 100%of channels are in the inactivated state, a standard steady-stateinactivation (SSIN) protocol is run using a series of fifteen 100ms-long depolarizing prepulses, incrementing in 10 mV steps, immediatelyfollowed by a 5 ms testing pulse to V_(max). This protocol also permitsdetermination of the holding potential at which all channels are in theresting state.

For compounds causing significant retardation of recovery frominactivation, an estimate of the affinity for the inactivated state ofthe channel (K_(i)) is generated using the following protocol. From thenegative, no residual inactivation, holding potential, the cell isdepolarized to the conditioning voltage for 2-5 seconds, returned to thenegative holding potential for 10-20 ms to relieve fast inactivation andthen depolarized to the test potential for ˜15 ms. This voltage protocolis repeated every 10-15 seconds, first to establish a baseline in theabsence of the test compound, then in the presence of the test compound.

After a stable baseline is established, the test compound is applied andblock of the current elicited by the test pulse assessed. In some cases,multiple cumulative concentrations are applied to identify aconcentration that blocked between 40-60% of this current. Washout ofthe compound is attempted by superfusing with control solution oncesteady-state block is observed. An estimate of the K_(i) is calculatedas follows:

K _(i)=[drug]*{FR/(1−FR)},  Eq. 1

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude. If multiple concentrations wereused, K_(i) is determined from the fit of a logistic equation to FRsplotted against corresponding drug concentrations.

In the alternative, the voltage clamp protocol to examine hNa_(v)1.7currents is as follows. After establishing the whole-cell configurationin voltage clamp mode, two voltage protocols were run to establish: 1)the holding potential; and 2) the test potential for each cell.

Resting Block:

To determine a membrane potential at which the majority of channels arein the resting state, a standard steady-state inactivation (SSIN)protocol is run using 100 ms prepulses×10 mV depolarizing steps. Theholding potential for testing resting block (V_(h1)) is typically 20 mVmore hyperpolarized than the first potential where inactivation isobserved with the inactivation protocol.

From this holding potential a standard I-V protocol is run to determinethe potential at which the maximal current is elicited (V_(max)). Thispotential is the test potential (V_(t)).

The compound testing protocol is a series of 10 ms depolarizations fromthe Vh1 (determined from the SSIN) to the V_(t) (determined from the I-Vprotocol) repeated every 10-15 seconds. After a stable baseline isestablished, a high concentration of a test compound (highestconcentration solubility permits or that which provides ˜50% block) isapplied and block of the current assessed. Washout of the compound isattempted by superfusing with control solution once steady-state blockwas observed. The affinity for the resting state of the channels iscalculated as follows:

K _(r)=[drug]*{FR/(1−FR)},  Eq. 3

where [drug] is the concentration of a drug, and

FR=I(after drug)/I(control),  Eq. 2

where I is the peak current amplitude and was used for estimatingresting block dissociation constant, K_(r).

Block of Inactivated Channels:

To assess the block of inactivated channels the holding potential isdepolarized such that 20-50% of the current amplitude is reduced whenpulsed to the same V_(t) as above. This is the second holding potential(V_(h2)). The magnitude of this depolarization depends upon the initialcurrent amplitude and the rate of current loss due to slow inactivation.The current reduction is recorded to determine the fraction of availablechannels at this potential (h).

h=I@V _(h2) /I _(max).  Eq. 4

At this membrane voltage a proportion of channels are in the inactivatedstate, and thus inhibition by a blocker includes interaction with bothresting and inactivated channels.

To determine the potency of the test compound on inactivated channels, aseries of currents are elicited by 10 ms voltage steps from V_(h2) toV_(t) every 10-15 seconds. After establishing a stable baseline, the lowconcentration of the compound is applied. In some cases, multiplecumulative concentrations will have to be applied to identify aconcentration that blocks between 40-60% of the current. Washout isattempted to re-establish baseline. Fractional responses are measuredwith respect to a projected baseline to determine K_(app).

K _(app)=[drug]*{FR/(1−FR)},  Eq. 5

where [drug] is the concentration of a drug.

This K_(app) value, along with the calculated K_(r) and h values, areused to calculate the affinity of the compound for the inactivatedchannels (K_(i)) using the following equation:

Ki=(1−h)/((1/K _(app))−(h/K _(r))).  Eq. 6

Voltage Protocols Automated Electrophysiology:

Similar voltage protocols are used as described above, however the testpotential (V_(t)) is set to a predetermined voltage. K_(app) isdetermined as described above.

Solutions and Chemicals:

For electrophysiological recordings the external solution is eitherstandard, HBSS supplemented with 10 mM HEPES (pH adjusted to 7.34 withNaOH and the osmolarity adjusted to 320) or Tyrodes salt solution(Sigma, USA) supplemented with 10 mM HEPES (pH adjusted to 7.4 withNaOH; osmolarity=320). The internal pipette solution contains (in mM):NaCl (10), CsF (140), CaCl2 (1), MgCl2 (5), EGTA (11), HEPES (10: pH7.4, 305 mOsm). Compounds are prepared first as series of stocksolutions in DMSO and then dissolved in external solution; DMSO contentin final dilutions did not exceed 0.3%. At this concentration, DMSO doesnot affect sodium currents. Vehicle solution used to establish base linealso contains 0.3% DMSO.

Data Analysis Manual Electrophysiology:

Data is analyzed off-line using Clampfit software (pClamp, v.8; AxonInstruments) and graphed using GraphPad Prizm (v. 4.0) software.

Data Analysis Automated Electrophysiology:

Data is analyzed off-line using Igor Pro (v 6.2.2.2; Wave Metrics, Inc.,Lake Oswego, Oreg.) and Microsoft XL (Microsoft Office 2010, v14×,Microsoft, Renton Wash.).

In Vivo Assay for Pain

Compounds of the Disclosure can be tested for their antinociceptiveactivity in the formalin model as described in Hunskaar et al., J.Neurosci. Methods 14: 69-76 (1985). Male Swiss Webster NIH mice (20-30g; Harlan, San Diego, Calif.) can be used in all experiments. Food iswithdrawn on the day of the experiment. Mice are placed in Plexiglassjars for at least 1 hour to acclimate to the environment. Following theacclimation period, mice are weighed and given either the compound ofinterest administered i.p. or p.o., or the appropriate volume of vehicle(for example, 10% Tween-80 or 0.9% saline, and other pharmaceuticallyacceptable vehicles) as control. Fifteen minutes after the i.p. dosing,and 30 minutes after the p.o. dosing mice are injected with formalin (20μL of 5% formaldehyde solution in saline) into the dorsal surface of theright hind paw. Mice are transferred to the Plexiglass jars andmonitored for the amount of time spent licking or biting the injectedpaw. Periods of licking and biting are recorded in 5-minute intervalsfor 1 hour after the formalin injection. All experiments are done in ablinded manner during the light cycle. The early phase of the formalinresponse is measured as licking/biting between 0-5 minutes, and the latephase is measured from 15-50 minutes. Differences between vehicle anddrug treated groups can be analyzed by one-way analysis of variance(ANOVA). A P value <0.05 is considered significant. Compounds areconsidered to be efficacious for treating acute and chronic pain if theyhave activity in blocking both the early and second phase offormalin-induced paw-licking activity.

In Vivo Assays for Inflammatory or Neuropathic Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of a testcompound when food is removed for 16 h before dosing. A control groupacts as a comparison to rats treated with a Compound of the Disclosure.The control group is administered the carrier as used for the testcompound. The volume of carrier administered to the control group is thesame as the volume of carrier and test compound administered to the testgroup.

Inflammatory Pain:

To assess the actions of Compounds of the Disclosure on the treatment ofinflammatory pain, the Freund's complete adjuvant (“FCA”) model ofinflammatory pain is used. FCA-induced inflammation of the rat hind pawis associated with the development of persistent inflammatory mechanicaland thermal hyperalgesia and provides reliable prediction of theanti-hyperalgesic action of clinically useful analgesic drugs (Bartho etal., Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670 (1990)).Prior to the injury, the animal is assessed for response to noxiousmechanical stimuli by determining the paw withdrawal threshold (PWT), orto noxious thermal stimuli by determining paw withdrawal latency (PWL),as described below (baseline PWT or PWL). Then, the left hind paw ofeach animal is administered a 50 μL intraplantar injection of 50% FCA.24 hour post injection, the PWT or PWL is again assessed(pre-administration PWT or PWL). Rats are then administered a singleinjection of either a test compound or 30 mg/Kg of a positive controlcompound (e.g., indomethacin). Responses to noxious mechanical orthermal stimuli are then determined 1, 3, 5 and 24 hours postadministration (post-administration PWT or PWL). Percentage reversal ofhyperalgesia for each animal is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}\mspace{14mu} {or}\mspace{14mu} {PWL}} \right)\end{bmatrix}} \times 100}$

Neuropathic Pain:

To assess the actions of the test compounds for the treatment ofneuropathic pain the Seltzer model or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats(Seltzer et al., Pain 43:205-218 (1990)). Partial ligation of the leftsciatic nerve is performed under isoflurane/O₂ inhalation anesthesia.Following induction of anesthesia, the left thigh of the rat is shavedand the sciatic nerve exposed at high thigh level through a smallincision and is carefully cleared of surrounding connective tissues at asite near the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture is inserted into the nerve with a 3/8 curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness is held within the ligature. The wound isclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. Following surgery, the wound area is dusted with antibioticpowder. Sham-treated rats undergo an identical surgical procedure exceptthat the sciatic nerve is not manipulated. Following surgery, animalsare weighed and placed on a warm pad until they recover from anesthesia.Animals are then returned to their home cages until behavioral testingbegins. The animals are assessed for response to noxious mechanicalstimuli by determining PWT, as described below, prior to surgery(baseline), then immediately prior to and 1, 3, and 5 hours afteradministration of either drug or vehicle, for the ipsilateral (injuredside) rear paw of the animal. Percentage reversal of neuropathichyperalgesia is defined as:

${\% \mspace{14mu} {reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}}{\begin{bmatrix}{\left( {{baseline}\mspace{14mu} {PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu} {PWT}} \right)\end{bmatrix}} \times 100}$

In the Chung model, the spinal nerve ligation (SNL) model of neuropathicpain is used to produce mechanical hyperalgesia, thermal hyperalgesia,and tactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anesthesia. Following induction of anesthesia a 3 cm incisionis made and the left paraspinal muscles are separated from the spinousprocess at the L₄-S₂ levels. The L₆ transverse process is carefullyremoved with a pair of small rongeurs to identify visually the L₄-L₆spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) is (are)isolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is (are)not manipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of theDisclosure or vehicle, for the left rear paw of the animal. The animalscan also be assessed for response to noxious thermal stimuli or fortactile allodynia, as described below. The Chung model for neuropathicpain is described in Kim et al., Pain 50(3):355-363 (1992).

Tactile Allodynia:

Sensitivity to non-noxious mechanical stimuli can be measured in animalsto assess tactile allodynia. Rats are transferred to an elevated testingcage with a wire mesh floor and allowed to acclimate for five to tenminutes. A series of von Frey monofilaments are applied to the plantarsurface of the hindpaw to determine the animal's withdrawal threshold.The first filament used possesses a buckling weight of 9.1 gms (0.96 logvalue) and is applied up to five times to see if it elicits a withdrawalresponse. If the animal has a withdrawal response, then the nextlightest filament in the series would be applied up to five times todetermine if it also could elicit a response. This procedure is repeatedwith subsequent lesser filaments until there is no response and theidentity of the lightest filament that elicits a response is recorded.If the animal does not have a withdrawal response from the initial 9.1gms filament, then subsequent filaments of increased weight are applieduntil a filament elicits a response and the identity of this filament isrecorded. For each animal, three measurements are made at every timepoint to produce an average withdrawal threshold determination. Testscan be performed prior to, and at 1, 2, 4 and 24 hours post drugadministration.

Mechanical Hyperalgesia:

Representative Compounds of the Disclosure can be tested in theSNL-induced mechanical hyperalgesia model in rats. Sensitivity tonoxious mechanical stimuli are measured in animals using the pawpressure test to assess mechanical hyperalgesia. In rats, hind pawwithdrawal thresholds (“PWT”), measured in grams, in response to anoxious mechanical stimulus are determined using an analgesymeter (Model7200, commercially available from Ugo Basile of Italy), as described inStein (Biochemistry & Behavior 31: 451-455 (1988)). The rat's paw isplaced on a small platform, and a punctate weight was applied in agraded manner up to a maximum of 250 grams. The endpoint is taken as theweight at which the paw is completely withdrawn. PWT is determined oncefor each rat at each time point. PWT can be measured only in the injuredpaw, or in both the injured and non-injured paw. Rats are tested priorto surgery to determine a baseline, or normal, PWT. Rats are testedagain 2 to 3 weeks post-surgery, prior to, and at different times after(e.g. 1, 3, 5 and 24 hr) drug administration. An increase in PWTfollowing drug administration indicates that the test compound reducesmechanical hyperalgesia.

In Vivo Assay for Anticonvulsant Activity

Compounds of the Disclosure can be tested for in vivo anticonvulsantactivity after i.v., p.o., or i.p. injection using any of a number ofanticonvulsant tests in mice or rats, including the maximum electroshockseizure test (MES). Maximum electroshock seizures are induced in maleNSA mice weighing between 15-20 g and in male Sprague-Dawley ratsweighing between 200-225 g by application of current (for mice: 50 mA,60 pulses/sec, 0.8 msec pulse width, 1 sec duration, D.C.; for rats: 99mA, 125 pulses/sec, 0.8 msec pulse width, 2 sec duration, D.C.) using aUgo Basile ECT device (Model 7801). Mice are restrained by gripping theloose skin on their dorsal surface and saline-coated corneal electrodesare held lightly against the two corneae. Rats are allowed free movementon the bench top and ear-clip electrodes are used. Current is appliedand animals are observed for a period of up to 30 seconds for theoccurrence of a tonic hindlimb extensor response. A tonic seizure isdefined as a hindlimb extension in excess of 90 degrees from the planeof the body. Results can be treated in a quantal manner.

Pharmaceutical Compositions

Compounds of the Disclosure can be administered to a mammal in the formof a raw chemical without any other components present. Compounds of theDisclosure can also be administered to a mammal as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.

Pharmaceutical compositions within the scope of the present disclosureinclude all compositions where a Compound of the Disclosure is combinedwith one or more pharmaceutically acceptable carriers. In oneembodiment, the Compound of the Disclosure is present in the compositionin an amount that is effective to achieve its intended therapeuticpurpose. While individual needs may vary, a determination of optimalranges of effective amounts of each compound is within the skill of theart. Typically, a Compound of the Disclosure can be administered to amammal, e.g., a human, orally at a dose of from about 0.0025 to about1500 mg per kg body weight of the mammal, or an equivalent amount of apharmaceutically acceptable salt or solvate thereof, per day to treatthe particular disorder. A useful oral dose of a Compound of theDisclosure administered to a mammal is from about 0.0025 to about 50 mgper kg body weight of the mammal, or an equivalent amount of thepharmaceutically acceptable salt or solvate thereof. For intramuscularinjection, the dose is typically about one-half of the oral dose.

A unit oral dose may comprise from about 0.01 mg to about 1 g of theCompound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dosecan be administered one or more times daily, e.g., as one or moretablets or capsules, each containing from about 0.01 mg to about 1 g ofthe compound, or an equivalent amount of a pharmaceutically acceptablesalt or solvate thereof.

A pharmaceutical composition of the present disclosure can beadministered to any animal that may experience the beneficial effects ofa Compound of the Disclosure. Foremost among such animals are mammals,e.g., humans and companion animals, although the disclosure is notintended to be so limited.

A pharmaceutical composition of the present disclosure can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, gender, health, and weight of therecipient, condition or disorder to be treated, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired.

In one embodiment, a pharmaceutical composition of the presentdisclosure can be administered orally and is formulated into tablets,dragees, capsules or an oral liquid preparation. In one embodiment, theoral formulation comprises extruded multiparticulates comprising theCompound of the Disclosure.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by injection.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered transdermally.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by the intravaginal route.

A pharmaceutical composition of the present disclosure can contain fromabout 0.01 to 99 percent by weight, and preferably from about 0.25 to 75percent by weight, of active compound(s).

A method of the present disclosure, such as a method for treating adisorder responsive to the blockade of sodium channels in an animal inneed thereof, can further comprise administering a second therapeuticagent to the animal in combination with a Compound of the Disclosure. Inone embodiment, the other therapeutic agent is administered in aneffective amount.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is well within the skilled artisan'spurview to determine the other therapeutic agent's optimaleffective-amount range.

Compounds of the Disclosure (i.e., the first therapeutic agent) and thesecond therapeutic agent can act additively or, in one embodiment,synergistically. Alternatively, the second therapeutic agent can be usedto treat a disorder or condition that is different from the disorder orcondition for which the first therapeutic agent is being administered,and which disorder or condition may or may not be a condition ordisorder as defined herein. In one embodiment, a Compound of theDisclosure is administered concurrently with a second therapeutic agent;for example, a single composition comprising both an effective amount ofa Compound of the Disclosure and an effective amount of the secondtherapeutic agent can be administered. Accordingly, the presentdisclosure further provides a pharmaceutical composition comprising acombination of a Compound of the Disclosure, the second therapeuticagent, and a pharmaceutically acceptable carrier. Alternatively, a firstpharmaceutical composition comprising an effective amount of a Compoundof the Disclosure and a second pharmaceutical composition comprising aneffective amount of the second therapeutic agent can be concurrentlyadministered. In another embodiment, an effective amount of a Compoundof the Disclosure is administered prior or subsequent to administrationof an effective amount of the second therapeutic agent. In thisembodiment, the Compound of the Disclosure is administered while thesecond therapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the Compound of the Disclosureexerts its therapeutic effect for treating a disorder or condition.

The second therapeutic agent can be an opioid agonist, a non-opioidanalgesic, a non-steroidal anti-inflammatory agent, an antimigraineagent, a Cox-II inhibitor, a β-adrenergic blocker, an anticonvulsant, anantidepressant, an anticancer agent, an agent for treating addictivedisorder, an agent for treating Parkinson's disease and parkinsonism, anagent for treating anxiety, an agent for treating epilepsy, an agent fortreating a seizure, an agent for treating a stroke, an agent fortreating a pruritic condition, an agent for treating psychosis, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, or an agent for treating depression, or a mixturethereof.

A pharmaceutical composition of the present disclosure is manufacturedin a manner which itself will be known in view of the instantdisclosure, for example, by means of conventional mixing, granulating,dragee-making, dissolving, extrusion, or lyophilizing processes. Thus,pharmaceutical compositions for oral use can be obtained by combiningthe active compound with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which can bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound can be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

The following examples are illustrative, but not limiting, of thecompounds, compositions, and methods of the present disclosure. Suitablemodifications and adaptations of the variety of conditions andparameters normally encountered in clinical therapy and which areobvious to those skilled in the art in view of this disclosure arewithin the spirit and scope of the disclosure.

EXAMPLES Example 1 Synthesis of 2,6-dichloropyrimidine-4-carboxamide(Compound 3)

A mixture of orotic acid mono hydrate (Compound 1) (34.828 g, 0.200 mol,Aldrich), phosphorus oxychloride (100 mL, 1.092 mol) and 20 drops of DMFwere heated at 110° C. overnight. After cooling the dark mixture wasdiluted with 500 mL hexanes and vigorously stirred. The hexane layer wasdecanted and quickly washed with water (1×100 mL) and brine (1×100 mL),and dried over MgSO₄. The organics were filtered and carefullyevaporated in vacuo to give Compound 2 as a light yellow liquid (26.13g). Yield: 62%. ¹H NMR (400 MHz, CDCl₃): δ 7.93 (s, 1H).

To a solution of Compound 2 (26.13 g, 123.6 mmol) in Et₂O (500 mL) wasadded a mixture of 0.5 M ammonia in dioxane (250 mL, 125 mmol) and DIPEA(22 mL, 126 mmol) dropwise over 50 min. After stirring at roomtemperature (RT) overnight the reaction mixture was concentrated invacuo to give a residue that was purified by flash chromatography (SiO₂,10-50% EtOAc/hexanes). The product fractions were evaporated in vacuo,and the resulting solid residue was triturated with 10 mL 10%EtOAc/hexanes and filtered to give Compound 3 as an orange crystallinesolid (9.743 g). Yield: 41%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (br s,1H), 8.16 (br s, 1H), 8.10 (s, 1H). LC/MS: m/z=192.2 [M+H]⁺ (Calc:191.4).

Example 2 Synthesis of Compounds 5 and 6

To a solution of Compound 3 (4.80 g, 25.0 mmol) in ACN (100 mL) wasadded (S)-3-aminopyrrolidin-2-one (Compound 4) (2.55 g, 25.54 mmol,Aldrich) and DIPEA (9.60 mL, 55.11 mmol). The mixture was heated at 50°C. overnight then concentrated in vacuo. The residue was purified byflash chromatography (SiO₂, 20-60% acetone/hexanes) to give Compound 5as a tan solid (4.79 g). Yield: 75%. LC/MS: m/z=256.2 [M+H]⁺ (Calc:255.4).

In a similar manner, Compound 6 was prepared.

LC/MS: m/z=244.2 [M+H]⁺ (Calc: 243.4).

Example 3 Synthesis of Compound 8

To a solution of Compound 5 (0.15 g, 0.59 mmol) and Compound 7 (0.145 g,0.65 mmol, Aldrich) in DMF (2.3 mL) was added K₂CO₃ (0.203 g, 1.467mmol). The reaction mixture was heated at 80° C. for 2 h, cooled to RT,and added dropwise into cold water with rapid stirring. The resultingsolid was collected by filtration, washed with water, dissolved in DCM,dried over Na₂SO₄, and purified by flash chromatography (SiO₂, 0-5%MeOH/DCM) to give Compound 8 as a light yellow solid (0.040 g). Yield:17%. ¹H NMR (400 MHz, CDCl₃): δ 7.68 (d, J=5.23 Hz, 1H), 7.30-7.22 (m,3H) 7.09 (d, J=5.92 Hz, 1H), 6.60 (s, 1H), 6.03-5.99 (bs, 1H), 5.62-5.56(bs, 1H), 5.53-5.50 (d, 1H), 5.13 (s, 2H), 4.75-4.68 (d, J=13.60 Hz,2H), 4.53-4.42 (bs, 1H), 3.46-3.41 (m, 2H), 3.39-3.29 (t, J=13.15 Hz,2H), 2.89-2.80 (m, 1H), 2.12-2.00 (quin, J=9.87 Hz, 1H), 1.95-1.84 (m,2H), 1.82 (s, 1H), 1.79 (s, 1H). LC/MS: m/z=409.2 [M+H]⁺ (Calc: 408.4).

In a similar manner, the following compounds were prepared:

Compound 9: ¹H NMR (400 MHz, DMSO-d₆): δ 7.69 (d, J=4.16 Hz, 1H), 7.35(t, J=9.87 Hz, 2H) 7.29-7.18 (m, 2H), 6.95 (d, J=5.48 Hz, 1H), 6.83 (d,J=5.48 Hz, 1H), 6.09 (d, J=14.25 Hz, 2H), 5.63 (d, J=4.38 Hz, 1H), 5.57(d, J=5.04 Hz, 1H), 4.78 (d, J=13.37 Hz, 2H), 4.54-4.45 (bs, 1H),3.46-3.40 (m, 2H), 3.30 (t, J=12.50 Hz, 2H), 2.89-2.80 (m, 1H),2.14-2.02 (m, 3H), 1.43 (d, J=13.37 Hz, 2H). LC/MS: m/z=405.1 [M+H]⁺(Calc: 404.5).

Compound 10: ¹H NMR (400 MHz, CD₃OD): δ 7.89 (d, J=8.55 Hz, 1H), 7.76(t, J=7.67 Hz, 1H) 7.61 (t, J=6.36 Hz, 2H), 6.58 (s, 1H), 4.98-4.91 (m,2H), 4.57 (t, 1H), 3.45-3.36 (m, 4H), 2.56-2.46 (m, 1H), 2.36-2.19 (m,3H), 1.79-1.69 (m, 2H). LC/MS: m/z=423.1 [M+H]⁺ (Calc: 422.4).

Compound 11: ¹H NMR (400 MHz, CD₃OD): δ 7.11 (t, J=8.77 Hz, 2H), 6.73(t, J=7.45 Hz, 1H), 6.64 (d, J=7.89 Hz, 2H), 6.60 (s, 1H), 4.72 (s, 2H),4.72-4.64 (m, 2H), 4.54 (t, J=10.09 Hz, 1H), 3.67 (t, J=12.06 Hz, 2H),3.41-3.34 (m, 2H), 2.69-2.55 (m, 2H), 2.53-2.44 (m, 1H), 2.31-2.18 (m,1H), 1.75-1.66 (m, 2H). LC/MS: m/z=451.2 [M+H]⁺ (Calc: 450.5).

Example 4

The following compounds were prepared according to literature procedures(including those provided infra.).

1-Bromo-4-(4-fluorophenoxy)benzene (Compound 22),1-(4-bromophenoxy)-3-fluorobenzene (Compound 23),1-bromo-4-(4-(trifluoromethyl)phenoxy)benzene (Compound 24) and1-(4-bromophenoxy)-3-(trifluoromethyl)benzene (Compound 25) wereprepared through procedures as those described in J. Med. Chem. 2008,51, 2845.

2-Chloro-5-(4-fluorophenoxy)pyridine (Compound 26) was prepared in theway as those described in WO 2009044160 A1.

2-Chloro-4-(4-(trifluoromethoxy)phenyl)pyridine (Compound 27) and2-chloro-4-(3-(trifluoromethoxy)phenyl)pyridine (Compound 28) wereprepared in accordance with procedures as those described in Bioorganic& Medicinal Chemistry Letters, 2013, 23(24), 6777-6783.

Example 5 2-Chloro-5-(4-(trifluoromethyl)phenoxy)pyridine (Compound 31)

A mixture of 2-chloro-5-hydroxypyridine (Compound 29) (1.7 g, 0.013 mol,Aldrich), 4-trifluoromethylphenyl boronic acid (Compound 30) (5.0 g,0.026 mol, Aldrich), and copper (II) acetate monohydrate (3.9 g, 0.020mol) was stirred at RT in DCM (60 mL). TEA (8 mL) and 4 A molecularsieves (20 g) were added. The suspension was stirred under air at RT for3 days and DCM (50 mL) was then added. The reaction mixture was stirredat RT for 25 min and filtered through Celite. The filtrate was washedwith water (1×100 mL), brine (1×100 mL) and dried over MgSO4. Theorganics were filtered and evaporated in vacuo. The residue was purifiedby flash chromatography (SiO2, 0-70% EtOAc/hexanes) to give Compound 31as a white solid (932 g, yield 26%): LC/MS: m/z=274 [M+H]⁺ (Calc:273.6).

In a similar manner, the following compounds were prepared:

2-Chloro-5-(3-(trifluoromethyl)phenoxy)pyridine (Compound 32): LC/MS:m/z=274 [M+H]⁺ (Calc: 273.6).

2-Chloro-3-(4-fluorophenoxy)pyridine (Compound 33): LC/MS: m/z=224[M+H]⁺ (Calc: 223.6).

Example 6 Synthesis of8-(5-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 17)

A mixture of 2-Chloro-5-[4-(trifluoromethyl)phenoxy]pyridine (Compound31) (925 mg, 3.38 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (Compound 34)(484 mg, 3.38 mmol, Aldrich) and t-BuOH (757 mg, 6.76 mmol) weresuspended in toluene (20 mL). To the suspension was added Pd₂(dba)₃ (72mg, 0.068 mmol) and followed by BINAP (105 mg, 0.169 mmol). The reactionmixture was heated at 100° C. in a microwave for 6 h. The reactionmixture was poured into EtOAc and filtered through Celite. The filtratewas evaporated in vacuo and the residue purified by flash chromatography(SiO2, 0-50% EtOAc/hexanes) to give Compound 35 (811 mg). Yield 63%

To a solution of Compound 35 (805 mg, 2.11 mmol) in THF (15 mL) wasadded 2N HCl (10 mL). The mixture was refluxed overnight, cooled to RT,and extracted with EtOAc (2×20 mL). The combined extracts were washedwith brine, dried over Na₂SO₄, and filtered through Celite. The filtratewas evaporated in vacuo and the residue purified by flash chromatography(SiO2, 0-50% EtOAc/hexanes) to give Compound 36 (639 mg). Yield 90%LC/MS: m/z=337 [M+H]⁺ (Calc: 336.3).

To a suspension of Compound 36 in EtOH (15 mL) stirred at roomtemperature was added ammonium carbonate (1.43 g, 14.89 mmol). Themixture was treated with a suspension of potassium cyanide (254 mg, 3.91mmol) in water (10 mL). The resulting mixture was heated at 80° C. for16 h. The reaction mixture was cooled to RT and the EtOH removed underreduced pressure. Water (20 mL) and EtOAc (20 mL) was added. The organicphase was separated and the aqueous phase was extracted with EtOAc (20mL). The combined extracts were washed with brine, dried over Na₂SO₄,and filtered through Celite. The filtrate was evaporated in vacuo andthe residue purified by recrystallization from a mixture of EtOAc andhexane to give Compound 17 as a white solid (635 mg): ¹H NMR (400 MHz,DMSO-d₆): δ 10.71 (s, 1H), 8.60 (s, 1H), 8.05 (d, J=3.08 Hz, 1H), 7.70(m, J=8.58 Hz, 2H), 7.46 (dd, J=9.13, 2.97 Hz, 1H), 7.09 (m, J=8.58 Hz,2H), 6.99 (d, J=9.24 Hz, 1H), 4.07-4.21 (m, 2H), 3.23-3.36 (m, 3H),2.48-2.53 (m, 1H), 1.77-1.90 (m, 2H), 1.61 (d, J=13.20 Hz, 2H). LC/MS:m/z=407.1 [M+H]⁺ (Calc: 406.4).

In a similar manner, the following compounds were prepared.

8-(4-(4-Fluorophenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 12)

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 2H), 8.53 (s, 2H), 7.08-7.27 (m,4H), 6.89-7.02 (m, 10H) 3.48-3.64 (m, 4H), 3.32 (s, 4H), 2.96-3.11 (m,4H), 2.48-2.55 (m, 9H), 1.83-2.02 (m, 4H), 1.63 (d, J=13.42 Hz, 4H).LC/MS: m/z=356.1 [M+H]⁺ (Calc: 355.4).

8-(4-(3-Fluorophenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 13)

¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 8.54 (s, 1H), 7.26-7.44 (m,1H), 6.94-7.07 (m, 4H), 6.89 (t, J=8.62 Hz, 1H), 6.68-6.79 (m, 2H),3.50-3.67 (m, 2H), 3.32 (s, 1H), 2.97-3.15 (m, 2H), 2.48-2.54 (m, 4H),1.87-2.00 (m, 2H), 1.64 (d, J=13.20 Hz, 2H). LC/MS: m/z=356.1 [M+H]⁺(Calc: 355.4).

8-(4-(3-(Trifluoromethyl)phenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 14)

¹H NMR (400 MHz, DMSO-d₆): δ 10.68 (br. s., 1H) 8.51 (s, 1H), 7.58 (t,J=7.92 Hz, 1H), 7.41 (d, J=7.70 Hz, 1H), 7.13-7.26 (m, 2H), 6.95-7.10(m, 4H), 3.46-3.71 (m, 2H), 3.32 (s, 2H), 3.06 (t, J=10.78 Hz, 2H),2.48-2.54 (m, 4H), 1.87-2.10 (m, 2H), 1.63 (d, J=13.20 Hz, 2H). LC/MS:m/z=406.0 [M+H]⁺ (Calc: 405.4).

8-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 15)

¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.59 (s, 1H), 8.19 (d,J=5.28 Hz, 1H), 7.82-7.98 (m, 2H), 7.48 (d, J=8.14 Hz, 2H), 7.13 (s,1H), 6.95 (dd, J=5.17, 1.21 Hz, 1H), 4.19-4.46 (m, 2H), 3.31-3.38 (m,3H), 2.48-2.54 (m, 6H), 1.74-1.91 (m, 2H), 1.59 (d, J=13.42 Hz, 2H).LC/MS: m/z=407.1 [M+H]⁺ (Calc: 406.3).

8-(5-(4-Fluorophenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 16)

¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.59 (s, 1H), 8.19 (d,J=5.28 Hz, 1H), 7.82-7.98 (m, 2H), 7.48 (d, J=8.14 Hz, 2H), 7.13 (s,1H), 6.95 (dd, J=5.17, 1.21 Hz, 1H), 4.19-4.46 (m, 2H), 3.31-3.38 (m,3H), 2.48-2.54 (m, 6H), 1.74-1.91 (m, 2H), 1.59 (d, J=13.42 Hz, 2H).LC/MS: m/z=357.1 [M+H]⁺ (Calc: 356.4).

8-(5-(3-(Trifluoromethyl)phenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 18)

¹H NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), 8.59 (s, 1H), 8.05 (d,J=2.86 Hz, 1H), 7.58 (t, J=7.86 Hz, 1H), 7.38-7.51 (m, 2H), 7.23 (s,1H), 7.22 (d, J=7.43 Hz, 2H), 6.99 (d, J=9.24 Hz, 1H), 4.06-4.21 (m,2H), 3.24-3.34 (m, 4H), 2.49-2.53 (m, 3H), 1.74-1.93 (m, 2H), 1.60 (d,J=13.20 Hz, 2H). LC/MS: m/z=407.1 [M+H]⁺ (Calc: 406.4).

8-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 19)

¹H NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 8.48 (s, 1H), 7.63 (d,J=8.80 Hz, 2H), 6.93-7.02 (m, 6H), 3.48-3.61 (m, 2H), 3.26 (s, 2H),2.93-3.08 (m, 2H), 2.42-2.46 (m, 1H), 1.80-1.93 (m, 2H), 1.57 (d,J=13.20 Hz, 2H). LC/MS: m/z=406.0 [M+H]⁺ (Calc: 405.4).

8-(3-(4-Fluorophenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 20)

¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 8.54 (s, 1H), 8.05 (dd,J=4.73, 1.43 Hz, 1H), 7.16-7.28 (m, 3H), 6.88-6.97 (m, 3H), 3.84-3.96(m, 2H), 3.33 (s, 1H), 3.18 (t, J=11.33 Hz, 2H), 2.48-2.53 (m, 1H),1.69-1.83 (m, 2H), 1.52 (d, J=13.20 Hz, 2H). LC/MS: m/z=357.1 [M+H]⁺(Calc: 356.4).

8-(4-(3-(Trifluoromethoxy)phenyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione(Compound 21)

¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.60 (s, 1H), 8.20 (d,J=5.28 Hz, 1H), 7.82 (d, J=7.46 Hz, 1H), 7.79 (s, 1H), 7.63 (t, J=8.03Hz, 1H), 7.45 (d, J=7.52 Hz, 1H), 7.17 (s, 1H), 6.97 (dd, J=5.28, 1.10Hz, 1H), 4.22-4.35 (m, 2H), 3.31-3.40 (m, 3H), 2.48-2.53 (m, 1H),1.78-1.99 (m, 2H), 1.60 (d, J=13.42 Hz, 2H). LC/MS: m/z=407.1 [M+H]⁺(Calc: 406.4).

Example 7

Representative Compounds of the Disclosure have been tested in the FLIPRor FLIPR^(TETRA)® assays and/or EP assays for sodium channel blockingactivity (as described above). Representative values obtained fromCoroNa™ Green AM Na⁺ Dye for Primary Fluorescence Assay and/or EP assaysare presented in TABLE 3, and representative values from membranepotential dye for alternative fluorescence assays and/or EP assays forare presented in TABLE 4.

TABLE 3 Evaluation of compounds as sodium channel (Na_(v)) blockersNa_(v)1.7 Activity (μM) Compound FLIPR assay No. IC₅₀ 8 3.918 ± 0.466 91.304 ± 0.124 10 3.860 ± 0.390 11 >20

TABLE 4 Evaluation of compounds as sodium channel (Na_(v)) blockersNa_(v)1.7(MP) Activity (μM) Compound FLIPR assay No. IC₅₀ 12 >20 131.536 ± 0.223 14 1.268 ± 0.380 15 0.872 ± 0.117 16 4.479 ± 1.040 171.730 ± 0.649 18 1.435 ± 0.492 19 >20 20 >20 21 1.979 ± 0.309

Having now fully described this disclosure, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations and otherparameters without affecting the scope of the disclosure or anyembodiment thereof.

Other embodiments of the disclosure will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference in their entirety.

1-17. (canceled)
 18. A compound of Formula A, or a pharmaceuticallyacceptable salt or solvate thereof:

Wherein a and b, each independently, are 0, 1, or 2, provided that atleast one of a and b is a value other than 0; n is 0, 1, or 2; o is O or1; m, each independently, is 0, 1, or 2; W¹ is —(CR^(5′)R^(6′))_(n)—U—;W² is —(CR^(7′)R^(8′))_(o)-G-; U is absent, N(R^(1a′)) or O, providedthat when n is 0, then U is N(R^(1a′)) or O; G is absent, N(R^(1b′)) orO, provided that when o is 0, then G is N(R^(1b′)) or O; R^(1′) andR^(2′), each independently, are H, optionally-substituted alkyl, alkoxy,cyano, alkenyl, carboxamido, and nitro; or R^(1′) and R^(2′), taken withthe carbon atom they are attached to, form a carbonyl group; R^(3′) andR^(4′), each independently, are H, optionally-substituted alkyl, alkoxy,cyano, alkenyl, carboxamido, and nitro; or R^(3′) and R^(4′), taken withthe carbon atom they are attached to, form a carbonyl group; R^(5′) andR^(6′), each independently, are H, alkyl, haloalkyl, —S(O)_(m)—R^(9′),alkoxy, haloalkoxy, amino, (alkyl)amino, (dialkyl)amino, carboxamido,cyano, (hydroxy)alkyl, (dihydroxy)alkyl, nitro, or sulfonamido; orR^(5′) and R^(6′), taken together with the carbon atom to which they areboth directly attached, form carbonyl, 3- to 8-membered optionallysubstituted heterocyclo, or 3- to 8-membered optionally-substitutedcycloalkyl; or R^(1′) and R^(5′), together with carbon atoms to whichthey are respectively attached, are fused to form a carbon-carbon doublebond; or R^(1′), R^(2′), one R^(5′), and one R^(6′), together withcarbon atoms to which they are respectively attached, are fused to formoptionally-substituted aryl or optionally-substituted 5- to 6-memberedheteroaryl; or one R^(5′), one R^(6′), R^(3′) and R^(4′), together withthe carbon atoms to which they are respectively attached, are fused toform optionally-substituted aryl or optionally-substituted 5- to6-membered heteroaryl, wherein said one R^(5′) and said one R^(6′) areattached to a same carbon atom; R^(1a′) is H, optionally-substitutedalkyl, optionally-substituted aryl, optionally-substituted cycloalkyl,optionally-substituted (alkoxy)carbonyl, carboxamido,optionally-substituted ((amino)alkyl)carbonyl, or optionally-substituted(alkyl)carbonyl; or R^(1a′) and R^(1′), taken together with the bondsthey are attached to, form a 5- to 8-membered optionally-substitutedheterocyclo; R^(7′) and R^(8′), each independently, are H, alkyl,haloalkyl, —S(O)_(m)—R^(9′), alkoxy, haloalkoxy, amino, (alkyl)amino,(dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl, (dihydroxy)alkyl,nitro, or sulfonamido; or R^(7′) and R^(8′), taken together with thecarbon atom to which they are attached, form 3- to 8-membered optionallysubstituted heterocyclo, or a 3- to 8-membered optionally-substitutedcycloalkyl; or R^(3′) and R^(7′), together with carbon atoms to whichthey are respectively attached, are fused to form a carbon-carbon doublebond; or R^(3′), R^(4′), one R^(7′), and one R^(8′), together withcarbon atoms to which they are respectively attached, are fused to formoptionally-substituted aryl or optionally-substituted 5- to 6-memberedheteroaryl, wherein said one R^(7′) and said one R^(8′) are attached toa same carbon atom; R^(1b′) is H, optionally-substituted alkyl,optionally-substituted aryl, optionally-substituted cycloalkyl,optionally-substituted (alkoxy)carbonyl, carboxamido,optionally-substituted ((amino)alkyl)carbonyl, or optionally-substituted(alkyl)carbonyl; or R^(1b′) and R^(3′), taken together with the bondsthey are attached to, form a 5- to 8-membered optionally-substitutedheterocyclo; A¹ is selected from the group consisting of: a)optionally-substituted 3- to 8-membered heterocyclo; b)optionally-substituted aryl; and c) optionally-substituted 6-memberedheteroaryl; A² is selected from the group consisting of: i) absent; ii)optionally-substituted 3- to 8-membered heterocyclo; iii)optionally-substituted aryl; and iv) optionally-substituted 6-memberedheteroaryl; X is absent, —O—, —N(R^(10′))—, —SO₂N(R^(11′))—, or —C(O)O—,provided that when A² is absent, then X is absent or —C(O)O—; R^(9′) isoptionally-substituted alkyl, optionally-substituted cycloalkyl,optionally-substituted heteroaryl, or optionally-substitutedheterocyclo; R^(10′) and R^(11′), each independently, are H oroptionally-substituted alkyl.
 19. The compound of claim 18, wherein aand b are both
 1. 20. The compound of claim 18, wherein A² isoptionally-substituted aryl or optionally-substituted 6-memberedheteroaryl.
 21. The compound of claim 18, wherein A² is selected fromthe group consisting of phenyl, pyridyl, pyrimidyl, and triazinyl, eachof which is optionally substituted.
 22. The compound of claim 18,wherein said compound is a compound of Formula B, or a pharmaceuticallyacceptable salt, or solvate thereof:

Wherein Q¹, Q², and Q³, each independently, are CH or N; X is absent,—O—, or —N(R^(10′))—; A¹ is optionally-substituted aryl oroptionally-substituted 6-membered heteroaryl; W¹ is—(CR^(5′)R^(6′))_(n)—U—; W² is —(CR^(7′)R^(8′))_(o)-G-; n is 0; o is 0;U is absent, N(R^(1a′)) or O, provided that when n is 0, then U isN(R^(1a′)) or O; G is absent, N(R^(1b′)) Or O, provided that when o is0, then G is N(R^(1b′)) Or 0; R^(1′) and R^(2′), each independently, areH, optionally-substituted alkyl, alkoxy, cyano, alkenyl, carboxamido, ornitro; or R^(1′) and R^(2′), taken with the carbon atom they areattached to, form a carbonyl group; R^(3′) and R^(4′), eachindependently, are H, optionally-substituted alkyl, alkoxy, cyano,alkenyl, carboxamido, or nitro; or R^(3′) and R^(4′), taken with thecarbon atom they are attached to, form a carbonyl group; R^(5′) andR^(6′), each independently, are H, alkyl, haloalkyl, alkoxy, haloalkoxy,amino, (alkyl)amino, (dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl,(dihydroxy)alkyl, or sulfonamido; or R^(5′) and R^(6′), taken togetherwith the carbon atom to which they are attached, form a 3- to 8-memberedoptionally substituted heterocyclo or a 3- to 8-memberedoptionally-substituted cycloalkyl; R^(1a′) is H, optionally-substitutedalkyl, optionally-substituted aryl, optionally-substituted(alkoxy)carbonyl, or carboxamido; or R^(1a′) and R^(1′), taken togetherwith the bonds they are attached to, form a 5- to 8-memberedoptionally-substituted heterocyclo; R^(7′) and R^(8′), eachindependently, are H, alkyl, haloalkyl, alkoxy, haloalkoxy, amino,(alkyl)amino, (dialkyl)amino, carboxamido, cyano, (hydroxy)alkyl,(dihydroxy)alkyl, or sulfonamido; or R^(7′) and R^(8′), taken togetherwith the carbon atom to which they are attached, form a 3- to 8-memberedoptionally substituted heterocyclo or a 3- to 8-memberedoptionally-substituted cycloalkyl; R^(1b′) is H, optionally-substitutedalkyl, optionally-substituted aryl, optionally-substituted(alkoxy)carbonyl, or carboxamido; or R^(1b′) and R^(3′), taken togetherwith the bonds they are attached to, form a 5- to 8-memberedoptionally-substituted heterocyclo; R^(10′) is H oroptionally-substituted alkyl; j is 0, 1, 2, or 3; R^(d) eachindependently is selected from the group consisting of: a) hydrogen; b)halo; c) nitro; d) cyano; e) hydroxy; f) amino; g) alkylamino; h)dialkylamino; i) optionally-substituted (heterocyclo)amino; j)haloalkyl; k) hydroxyalkyl; l) alkoxy; m) haloalkoxy; n) alkoxyalkyl; o)carboxamido; p) optionally-substituted (heterocyclo)alkyl; q)optionally-substituted (cycloalkyl)alkyl; r) (alkoxy)carbonyl; s) —COOH;t) (carboxamido)(hydroxy)alkyl; and u) optionally-substituted((heterocyclo)amino)alkyl. 23-24. (canceled)
 25. The compound of claim18, wherein R^(1′) and R^(2′), taken with the carbon atom they areattached to, form a carbonyl group.
 26. The compound of claim 25,wherein R^(3′) and R^(4′) are both H; or R^(3′) and R^(4′), taken withthe carbon atom they are attached to, form a carbonyl group.
 27. Thecompound of claim 22, wherein at least one of Q¹, Q² and Q³ is CH. 28.The compound of claim 18, wherein A¹ is optionally-substituted phenyl oroptionally-substituted 6-membered heteroaryl.
 29. The compound of claim18, wherein said compound is a compound of Formula C, or apharmaceutically acceptable salt, or solvate thereof:

Wherein Q³ is CH or N; X is absent or —O—; U is N(R^(1a′)) or O; G isN(R^(1b′)) or O; R^(1a′) is H, alkyl, or aryl, wherein each of saidalkyl and said aryl is optionally substituted by one to threesubstituents independently selected from the group of halogen, hydroxy,carboxamido, amino, alkylamino, (heterocyclo)amino, alkoxy, haloalkoxy,and haloalkyl; R^(1b′) is H, alkyl, or aryl, wherein each of said alkyland said aryl is optionally substituted by one to three substituentsindependently selected from the group of halogen, hydroxy, carboxamido,amino, alkylamino, (heterocyclo)amino, alkoxy, haloalkoxy, andhaloalkyl; R^(d) is selected from the group consisting of: a) hydrogen;b) halo; c) amino; d) alkylamino; e) dialkylamino; f)optionally-substituted (heterocyclo)amino; g) haloalkyl; h)hydroxyalkyl; i) alkoxy; j) haloalkoxy; k) alkoxyalkyl; l) carboxamido;m) optionally-substituted (heterocyclo)alkyl; n)(carboxamido)(hydroxy)alkyl; and o) optionally-substituted((heterocyclo)amino)alkyl; R^(e) and R^(f) independently are selectedfrom the group consisting of: a) hydrogen; b) halo; c) hydroxy; d)amino; e) alkylamino; f) dialkylamino; g) optionally-substituted(heterocyclo)amino; h) haloalkyl; j) hydroxyalkyl; k) alkoxy; l)haloalkoxy; m) carboxamido; and o) optionally-substituted(heterocyclo)alkyl.
 30. The compound of claim 29, wherein R^(d) is H,carboxamido, or hydroxyalkyl.
 31. The compound of claim 29, whereinR^(e) is H, and R^(f) is selected from the group consisting of a) halo;b) amino; c) alkylamino; d) dialkylamino; e) (heterocyclo)aminooptionally-substituted by one to two substituents independently selectedfrom the group of halo, alkyl, haloalkyl, alkoxy, haloalkoxy, andcarboxamido; f) haloalkyl; g) hydroxyalkyl; h) alkoxy; i) haloalkoxy; j)carboxamido; and k) (heterocyclo)alkyl optionally-substituted by one totwo substituents independently selected from the group of halo, alkyl,haloalkyl, alkoxy, haloalkoxy, and carboxamido.
 32. The compound ofclaim 22, wherein said compound is a compound of Formula D:

or a pharmaceutically acceptable salt, or solvate thereof.
 33. Thecompound of claim 22, wherein said compound is a compound of Formula E:

or a pharmaceutically acceptable salt, or solvate thereof. 34-38.(canceled)
 39. The compound of claim 18 selected from the groupconsisting of:8-(4-(4-fluorophenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(4-(3-fluorophenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(4-(3-(trifluoromethyl)phenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(4-(4-(trifluoromethoxy)phenyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(5-(4-fluorophenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(5-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(5-(3-(trifluoromethyl)phenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(3-(4-fluorophenoxy)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione;8-(4-(3-(trifluoromethoxy)phenyl)pyridin-2-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione; and(S)-2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)-6-((2-oxopyrrolidin-3-yl)amino)pyrimidine-4-carboxamide;and a pharmaceutically acceptable salt, or solvate thereof.
 40. Apharmaceutical composition, comprising the compound of claim 18, or apharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier. 41-44. (canceled)
 45. A method fortreating pain in a mammal, comprising administering an effective amountof a compound as claimed in claim 18 or a pharmaceutically acceptablesalt, or solvate thereof, to a mammal in need of such treatment. 46.(canceled)
 47. The method of claim 45, wherein said method is forpreemptive or palliative treatment of pain.
 48. The method of claim 46,wherein said pain is selected from the group consisting of chronic pain,inflammatory pain, neuropathic pain, acute pain, and surgical pain. 49.A method of modulating sodium channels in a mammal, comprisingadministering to the mammal at least one compound as claimed in claim18, or a pharmaceutically acceptable salt, or solvate thereof.
 50. Themethod of claim 49, wherein Nav1.7 sodium channel is modulated. 51-53.(canceled)